Vascular Biology on Michael’s Domain

Just another type of fish

Wed, 12 Nov 2025 00:00:00 +0000

I still dream of improving my Finnish language skills, and as a consequence, I occasionally do irrational things. Now, with much help from two amazingly patient editors, I have tried to write a popular science article in Finnish about our scientific excursion into fish biology territory. The article just appeared in the mene & tiedä online magazine of the Young Academy Finland ( Nourten Tiedeakatemia ).

ADAMTS18 regulates ECM turnover via fibronectin cleavage

Tue, 04 Nov 2025 00:00:00 +0000

The maintenance of the specialized blood vessels in intestinal villi had been the topic of a Nature Communications paper from the Petrova lab ( https://doi.org/10.1038/s41467-022-31571-2 ). Maintaining the polarity of the nutrient-absorbing vessels required a differential exposure to VEGFA, which was maintained by specialized cells producing the right amount of fibronectin. The previously orphan ADAMTS18 was the protease that appeared instrumental in the proteolytic maturation of fibronectin. Now, a publication from the University of Eastern Finland analyzed the ADAMTS18 fibronectin connection in more detail: https://doi.org/10.1016/j.jbc.2025.110844 . Fibronectin normally does not exist as a single molecule, but it forms fibrils that are essential building blocks of the extracellular matrix. ADAMTS18 removes a critical part of the fibronectin molecule, thus preventing it from forming fibrils. This establishes ADAMTS18 as an important player not only in endothelial cell biology, but potentially in many other contexts in which fibronectin-containing extracellular matrix is involved. Fibronectin, as a major component of the provisional matrix, is crucial during wound healing and in the ECM maintenance of organs like the lungs. Consequently, there are many interesting avenues opening up to look at additional specific functions for ADAMTS18. Congrats, Maria, for this important contribution to our understanding of another ADAMTS family member!

Delivery still limits VEGF therapy

Fri, 12 Sep 2025 00:00:00 +0000

Simply injecting a lab-made growth factor into the body isn’t enough to copy what the body does naturally. That’s because our own growth factors are released in the right place, at the right time, and in the right amount, and their levels are constantly adjusted using feedback loops.

An impossible overlap-extension PCR

Sat, 21 Jun 2025 00:00:00 +0000

A PhD student of mine asked me about plasmid maps for several DNA constructs that I had created some 20 years ago. Since SnapGene did not exist at the time, I had used the now obsolete GeneConstructionKit2. I performed many clonings at the time, but I did not continue generating maps for all of them. The GCK2 format does not allow for easy annotation. You needed a separate program for comprehensively annotating the plasmids, and this data was saved in a separate file, the so-called “illustration” file: what could possibly go wrong? Yesterday, I ended up digging out my old lab notebooks and retracing about 10 old clonings in SnapGene. However, I was unable to simulate one of the assemblies because SnapGene was too conservative in disallowing “bad” PCR primers to function. I had performed overlap-extension PCR to introduce a mutation into the mouse VEGF-D cDNA. The homologous mutation had been introduced into human VEGF-D before, and I therefore had the primers for the human sequences. Mouse and human VEGF-D are very similar. The primers designed to amplify the human PCR were not perfect when using mouse cDNA as a template, but none of the differences would result in amino acid changes. So I attempted the PCR with a primer that had a mismatch in the third nucleotide from the 3’-end. The PCR was successful, but even when I lowered the hybridisation parameters to the least stringent settings, SnapGene would not anneal this primer to my template. To simulate cloning in SnapGene and generate a map, I needed to introduce a mutation into my primer and then reverse the mutation after the overlap extension PCR. I guess I need to file a bug report (or would this be a feature request?). It seems appropriate that the program should be able to allow annealing of primers that do anneal in reality…

VEGFC-loaded Lignin Nanoparticles

Thu, 24 Apr 2025 00:00:00 +0000

Vascular Endothelial Growth Factor C (abbreviated either VEGFC or VEGF-C) has been used in several preclinical models in regenerative medicine. Its potential applications range from repairing damaged heart tissue to treating neurodegenerative disorders . While repairing damaged hearts and brains is not realistic at this moment, VEGFC does offer a glimmer of hope for patients with lymphedema — a chronic condition that presently can only be treated symptomatically. Yet, despite promising preclinical and even some clinical trial data, one key hurdle remains: effective delivery.The current frontrunner, adenoviral VEGFC (AdVEGFC) gene therapy, had progressed to phase II clinical trials, but the results were inconclusive . One possible explanation is that the amount or the duration of VEGFC production by AdVEGFC is insufficient. Its rapid inactivation by the immune system is a double-edged sword, making it a safe, but perhaps not very potent drug. This shortfall has sparked interest in novel delivery systems that bypass the immune system while providing controlled and sustained release.In our latest preprint , we explore the potential of lignin nanoparticles (LNPs) as carriers for VEGFC, from synthesis to stability. Why lignin? Lignin, a major component of plant cell walls, is the second most abundant biopolymer on planet Earth, and it can be extracted from many different sources and synthesized into nanoparticles.Our stability tests revealed that VEGFC is relatively stable on its own. It easily survives weeks of storage at elevated temperatures, and we have kept it at 4°C for a year without any significant loss of activity. It is also relatively stable against proteolytic attacks. It is not degraded by trypsin or thermolysin, and even withstands limited exposure to proteinase K. However, freezing and thawing cause it to lose activity (one cycle is acceptable, but after 32 cycles, it has lost most of its activity). Therefore, nanoparticle delivery might not be critical for protecting VEGFC from degradation, but sustained and delayed release would be its major advantage.We loaded VEGFC onto the particles and evaluated its release profile. Our findings indicate not only successful encapsulation but also a delayed release pattern, suggesting that LNPs could serve as a slow-release depot for VEGFC. We discovered that VEGFC can hang around for a long time even on its own, as the difference between naked VEGFC and LNP-delivered VEGFC was less than we had expected. In a modified Ba/F3-VEGFR3/EpoR bioassay, naked VEGFC sustained cell survival and proliferation for more than a week, even though at the later time points, not to the same levels as LNP-bound VEGFC. Based on previous studies, we attribute the innate ability of VEGF-C to “hang around for a long time” to its affinity for specific extracellular matrix components and cell surface molecules such as heparan sulfate proteoglycans. Even though most of these interactions are mediated by the silk-homology domain of VEGFC (which was absent in our study, which used mature VEGFC), some of these interaction capabilities also seem to remain in mature VEGFC.With this study, we dipped our toes for the first time into nanoparticle-based delivery of biologics. Our work supports the feasibility of LNPs as an alternative to viral vectors. However, there is room for improvement. One way to improve the delayed release is to modify VEGFC (as was done by Güç et al ). However, instead of modifying a cDNA that codes for mature VEGF-C (as Güç et al. did), it might make sense to try pro-VEGFC. After all, pro-VEGFC is the endogenous, inactive “latent form” of VEGFC. That’s what we’ll try next. Check out the full preprint for detailed methodology and data! Link to the preprint: https://doi.org/10.1101/2025.04.23.649697

Billion-dollar gamble

Fri, 28 Feb 2025 00:00:00 +0000

Last December, Forbes published a feature article about Megan Baldwin’s work to improve the antiangiogenic treatment of eye diseases. I hope she wins her billion-dollar gamble not only because the drug in question was invented here at the University of Helsinki. The drug is called OPT-302 or with its INN name sozinibercept. The patent lists Kari Alitalo and me as the inventors. The drug was initially designed (under the name VGX-300) for cancer treatment, but - perhaps luckily - never really took off as such because it inhibits not only VEGF-D but also VEGF-C, which is needed in the body’s immune response against the cancer. So far, nobody has been able to separate the prometastatic and the proimmunogenic propeties of VEGF-C.

Our lab won't go bancrupt in 2025!

Fri, 29 Nov 2024 00:00:00 +0000

Our lab has been so unlucky with its recent grant applications that I was already seriously considering alternative career paths. Like becoming a tram driver. Helsinki and its surrounding cities are expanding their tram networks, and good drivers are rare. However, the Cancer Foundation Finland has now ended our unlucky streak! Although it is only a modest amount, I am hopeful for the future. Not all research is equally expensive: some methods need more money than others, and ours are at the budget end of that spectrum. What project got funded? Well, it’s not our novel protein expression system, but a project to answer a question that has been bugging many vascular biology researchers since 2001, when the Achen/Stacker lab published a paper showing that mouse and human VEGF-D do NOT share the same receptors, but that mouse VEGF-D does not bind mouse VEGFR-2 ( Baldwin et al., 2001 ). We showed in 2011 and 2019 , that the proteolytic activation of VEGF-D by cathepsin D leads to a loss of all VEGFR-3 binding in human VEGF-D. If this was true for mouse VEGF-D as well, it would be a growth factor without a receptor! This is not impossible, but it would be exceptional. It is important to get these molecular details right because we are testing our future cancer drugs always in mice. If there is a big difference in the angiogenic signaling between mice and men, this could render much mouse data very difficult to interpret and perhaps even explain why drugs that work well in mice fail in humans. Notably, among all drugs, oncology drugs have the worst success rates in clinical trials. There is reasonable evidence to believe that VEGF-D is the “bad boy” in the VEGF family, i.e., the one that is responsible for cancers developing resistance against antiangiogenic cancer therapies, that are based on blocking VEGF-A. In any case, a big shout-out to the Cancer Foundation Finland! Read here about the award.

What do we really know about lipedema?

Mon, 09 Sep 2024 00:00:00 +0000

Lipedema is an accumulation of subcutaneous fat, mainly in the lower body, which is resistant to weight loss and occurs almost exclusively in women. It is often painful, prone to bruising and is thought to have a genetic component, which is likely triggered by hormonal changes. Although lipoedema was recognised as a condition more than 80 years ago, our understanding of the condition and its aetiology remains incomplete. This is due in no small part to the fact that lipoedema has only recently been included in the official classification of diseases. Virtually all aspects of the condition are controversial, starting with its classification. The symptoms of lipoedema overlap with those of obesity, lipodystrophy, lymphoedema and connective tissue disorders. There are as yet no specific tests, and due to the uncertainty surrounding diagnosis, there is also considerable uncertainty regarding the prevalence of lipoedema, with estimates varying widely from 1 in 75,000 to 39 per cent of all women. Many hypotheses have been put forward regarding the cause of lipoedema, including that it is a lipid metabolism disorder, a connective tissue disorder, or an inflammatory or immune-mediated disease. A definitive cause has not yet been identified, and the search for ‘lipoedema genes’ has so far yielded no conclusive results, with the exception of individual genes that play a role in only a small proportion of all patients.

Do fish have difficulty breathing?

Fri, 28 Jun 2024 00:00:00 +0000

Fish are breathing with their gills, but this is literally, for many of them, only half of the story. The difficulty of extracting oxygen from water is the single most defining force that shapes fish evolution. Land animals are mostly exposed to the same oxygen concentration, but fish need to operate in waters of vastly different and rapidly changing oxygen content. Moreover, water contains much less oxygen than air, and the diffusion of oxygen in water is magnitudes slower than the diffusion of oxygen in air. Therefore, fish evolution was forced to come up with creative ways to

Do fish have lymphatics?

Sat, 27 Jan 2024 00:00:00 +0000

Read the whole back story in our preprint: https://doi.org/10.20944/preprints202312.2119.v1 . It isn’t easy to believe that the scientific community cannot agree on whether zebrafish have a lymphatic vascular system. Zebrafish is one of the most successful model organisms in biology, and one would assume that we know its overall vascular setup. However, starting with W. Vogel in 1981 ( https://doi.org/10.1515/znc-1981-5-627 ), many fish physiologists subscribe to the notion that there are no lymphatics in fish, and most contemporary fish physiology textbooks have appropriated this point of view. At the same time, solid publications from multiple labs show that lymphatic vessels exist in fish ( https://doi.org/10.1038/nm1427 , https://doi.org/10.1016/j.cub.2006.05.026 ). What is going on? When the Yaniv lab published in 2022 that embryonic lymphatics in zebrafish can transdifferentiate into blood vessels ( https://doi.org/10.1038/s41586-022-04766-2 ), it suddenly appeared possible to unite the two contradictory views. In a nutshell: In most fish, an embryonic lymphatic system transdifferentiates during development into blood vessels that form a specialized subcompartment of the cardiovascular system (the so-called secondary vascular system). The degree of transdifferentiation seems quite variable between fish species, and some vessels - notably the thoracic duct - might retain a hybrid phenotype.As so often is the case in top journals, the original article by Das et al. neither discussed the 100-year-old controversy nor the ramifications of its landmark findings. Even though Kari Alitalo and I did so in a short commentary ( https://rdcu.be/cOjJ0 ), more space is needed to do justice to the topic. Although the controversy about piscine lymphatics is far from settled, it appears important to record the current status of the discussion in the scientific literature. Moreover, we wanted to describe a high-likelihood consensus model against which to plan future experiments. The result is an extended review; we hope you’ll enjoy reading it. If you find something that you don’t like, by all means, let us know! Especially if you can back up your critique with data or sound arguments. We sent the manuscript for review and are happy to improve it based on your input.

Congratulations, Dr. Khushbu Rauniyar!

Sat, 10 Jun 2023 00:00:00 +0000

Defending a PhD thesis is a BIG thing in Finland, and you just did it. Unlike the rest of the world (perhaps except for Sweden), no other country requires as much demonstration of perseverance from PhD candidates as Finland does. On average, it takes four publications and 7 years. The long duration and the lack of well-defined requirements are two problems the Finnish Ministry of Education wants to address over the next few years to level the playing field for Finnish PhD graduates in the international job market. Completing a PhD in Finland takes a lot of Sisu. Sisu is a Finnish word which cannot be translated into any other language, but the recent movie with the same title can give you an idea. Wikipedia defines Sisu as extraordinary determination in the face of extreme adversity .In the “old times”, drugs were discovered based on their effects while not knowing their mechanism of action. This paradigm is more and more turned on its head. Researchers try to understand the mechanism that leads to disease before they start developing or finding a drug. Much of Khushbu’s thesis is about better understanding the mechanisms that govern the action of the primary lymphangiogenic growth factor VEGF-C: The evolutionary origin, activation, and potential as a drug target . Prof. Eckhard Lammert did a great job as the opponent, and Prof. Kari Keinänen did the same as the custos. Dear Khushbu , we wish you all the best for your next big project!

Cutting-edge vascular biology continues at the Wihuri Research Institute

Wed, 10 May 2023 00:00:00 +0000

Taija Mäkinen has been appointed to become the Wihuri Research Institute (WRI) Director starting in 2024. Like the current director Kari Alitalo , Taija has outstanding expertise in lymphatic vascular biology. Taija is currently doing research in Sweden at Uppsala University . With her contributions, she has revolutionized our understanding of how lymphatic vessels form and grow ( 10.1016/j.celrep.2015.02.026 , 10.1161/CIRCRESAHA.116.306170 ).The Wihuri Research Institute , located at Biomedicum Helsinki, was founded and is funded by the Jenny and Antti Wihuri Foundation . It focuses on cardiovascular and vascular biology. This research is essential for the development of new treatments for heart disease. However, blood and lymphatic vessels penetrate nearly all body organs and play a role in almost all diseases, including inflammatory and infectious diseases, neurodegenerative diseases, cancer, and vascular malformations or hypoplasia. Therefore, the research done at the WRI opens avenues for treating many diseases beyond heart disease. The Board of Trustees of the Jenny and Antti Wihuri Foundation has made an excellent choice, even though I am biased for many reasons. I do similar research, and I worked in the same lab as Taija during our Ph.D. education. Unnecessary to mention that Taija graduated faster than I did …

OMG: T. rex did not have VEGF-B!

Wed, 05 Apr 2023 00:00:00 +0000

Our work on the evolutionary origin of the PDGF and VEGF growth factors has just been published in Angiogenesis: https://doi.org/10.1007/s10456-023-09874-9 . We analyzed both PDGFs and VEGFs, but our focus was naturally on the VEGF side of things. It’s just a coincidence that the PDGFs happened to be a subgroup of the VEGFs and not vice versa, but that’s of course just our biased point of view :-)Since we do lymphatic research, we can proudly announce that the phylogenetic oldest VEGF likely resembled VEGF-C and featured the enigmatic silk homology domain. It makes intuitive sense (and had been proposed before by Jörg Wilting), because the most simple vascular systems that we know of are the so-called hemolymph systems (e.g., in insects), which share many features with the lymphatic system.With this publication, we did not do something exceptional that only a few can do. We did something everybody could do but nobody had done so far: looking systematically at which animals have which PDGFs and VEGFs. Actually, we did something new: we developed a crowdsourcing method for classifying PDGFs and VEGFs. Instead of asking people, we asked databases. There are many PDGF-like and VEGF-like sequences in databases, which are only recognizable as such by the homology of their amino acid sequence. In order to know whether we are dealing, e.g., with a VEGF-C or a VEGF-D, we are running many (PSI)BLAST searches, and then we tally up the majority opinion (as determined by the top hits).Many surprises waited for us after the bioinformatics script had finished its job after two weeks of finding and comparing PDGF- and VEGF-like sequences:

Bioactive VEGF-C from E. coli without in-vitro folding!

Fri, 28 Oct 2022 00:00:00 +0000

Our article Bioactive VEGF-C from E. coli has been published in Scientific Reports. Read here: https://doi.org/10.1038/s41598-022-22960-0.As a matter of fact, I did the first experiments expressing VEGF-C in E. coli in 1999, but never got active protein. In the following 15+ years, we exclusively used eukaryotic cells (yeast, S2/Sf9/Hi5 insect cells, CHO) to produce VEGF-C. We reactivated the “VEGF-C in E. coli” project a few years back and we finally reached our goal last year. However, it was much more work than we originally anticipated. In the beginning, all attempts went South, and to rescue the project, we developed an in-vitro folding protocol. It was perhaps more luck than ability that we stumbled upon a combination of solubility tag and redox-modified E. coli strain that can pull off the trick to produce directly bioactive VEGF-C without the need for an in-vitro folding step. We decided to include also our unsuccessful attempts (CyDisCo and periplasmic expression) in the results section to avoid the file drawer effect.

Making the cut: Why VEGF-C != VEGF-C

Wed, 28 Sep 2022 00:00:00 +0000

Yesterday, I talked about VEGF-C in the Zoom Lymphatic Seminar series, which is organized by Young Kwon Hong . Since there was not much time to ask questions, I am happy to answer them via email. If you have missed the link to the presentation slides, here it is: https://mjlab.fi/c . The take-home message: Many different mature forms of VEGF-C can be generated from pro-VEGF-C by proteolytic processing (and the same is true for VEGF-D). These forms behave VERY differently from each other. The extreme case is activation by Cathepsin D (CTSD): When activated by CTSD, VEGF-C becomes almost exclusively lymphangiogenic, while after activation by the same protease, VEGF-D becomes exclusively angiogenic. The detection of CTSD-activated VEGF-C is difficult because all well-functioning antibodies recognize epitopes N-terminal to the cleavage site (or they straddle the cleavage site). The second talk was by Barbara Garmy-Susini , and her topic was a nice fit since she talked about using VEGF-C in the therapy of lymphedema. But as we know already from VEGF-A, vascular growth factors alone might be not sufficient to generate a functional vasculature…

The evolution of PDGF/VEGF growth factors

Thu, 22 Sep 2022 00:00:00 +0000

We have uploaded a preprint of our most recent manuscript about the evolution of PDGF/VEGF growth factors to bioRxiv. We comprehensively analyzed the PDGF/VEGF part of the proteome in all animal species for which data is available. We have had some of this data already for a while, but now we enhance it with a detailed look at fishes. The vascular biology of fishes has become even more facinating after the publication of Das et al. earlier this year ( read more about this exceptional piece of work ).The remarkable heterogeneity of vascular systems in fishes seems to be supported by a similar extensive heterogeneity at the molecular level. Often, but not always can this genetic heterogeneity be traced back to whole genome duplications. Fishes tolerate full genome duplications better than mammals. At least there have been quite a few such duplications in various branches of the fish phylogenetic tree resulting in polyploid or even tetraploid species. That has resulted in some fish species featuring 4 times as many PDGF/VEGF genes compared to humans, and much more opportunities to diversify the functions of these molecules.The very first PDGF/VEGF-like molecule appeared likely more than 800 Million years ago during the Precambrian period when marine organisms started to show signs of tissue organization. If we set out to reconstruct this molecule, it would look remarkably similar to a modern VEGF-C. Specifically the C-terminal “silk homology domain” seems to have been invented early on in evolution. In fact, a large number of extant morphologically simple organisms feature such VEGF-C-like molecules still today (e.g. the nematode C. elegans). Beyond these insights into the evolution of PDGFs and VEGFs, there are some useful take-home messages for vascular biologists: For example, we did not find any functional VEGF-B genes in birds. Similarly, there seem to be no PlGFs in amphibians. Then, on the other hand, the VEGF-Fs - identified from snake venoms - appear to exist more broadly also in non-venomous lizards. This poses some limitations on some animal models (Xenopus, CAM assay), but it would be nice to know what VEGF-F is doing in geckos…Have a look at the manuscript and please comment or criticize, if you have any thoughts! The idea is to make this manuscript still a bit better before submitting it to a journal for the traditional peer-review.

"Bioactive VEGF-C from E. coli cytoplasm" preprint online

Fri, 01 Jul 2022 00:00:00 +0000

The preprint of our manuscript is online. We show how to produce bioactive mature VEGF-C in the cytoplasm of E. coli bacteria without the need for a folding step. It took us quite a while to get there, and we tried many things that did not work before we found a way how to do it. We describe also the methods that failed. It looks as if VEGF-C has simply too many cysteine residues that all have to pair up in the correct configuration. In the same manuscript, we also report a workable refolding method. Please have a look and give us some feedback: https://www.researchsquare.com/article/rs-1776636/v1 .

Lymphatics as the origin of the fish secondary vascular system

Thu, 26 May 2022 00:00:00 +0000

In zebrafish, the blood vessels of the anal fin develop from lymphatics by transdifferentiation. Karina Yaniv presented unorthodox, but very compelling data supporting this conclusion last September at the Kloster Seeon Angiogenesis meeting .Now her paper has been published in Nature .

KLK3: tumorigenic or not?

Wed, 22 Dec 2021 00:00:00 +0000

We have just published our latest review about the role of KLK3 as an activator of VEGF-C and VEGF-D in prostate cancer . Prostate cancer is one of the most common cancers in males. It is not a question of whether you will get it but only when. Once you reach your 80s, the likelihood of you having prostate cancer is bigger than not having it. In a 2013 autopsy study of Japanese males , who died of other causes, 59% of those older than 80 had prostate cancer. It is likely that many of these cases were indolent and would never have caused any problems. Only a few of them might have become symptomatic had these men lived longer. So, there is a significant interest in distinguishing those cancers that are going to cause problems. Many prognostic markers have been proposed to do exactly that: to predict which cancers would become problematic.From the vascular biology point of view, angiogenesis and lymphangiogenesis are two hallmarks of cancers that have been previously proposed to have prognostic value. When we stumbled upon the fact that prostate-specific antigen (PSA, also known as KLK3) is able to activate VEGF-C and VEGF-D , we thought that this might have significance for prostate cancer. Meanwhile, further research has clarified some questions, and it really seems to be that both VEGF-C and VEGF-D are involved in cancer progression. it is not clear yet which proteases are responsible for the activation of VEGF-C and VEGF-D in real human cancers. KLK3- or Cathepsin D (CTSD)-activated VEGF-D might be a possible cause of the resistance of tumors to bevacizumab (Avastin) treatment. The consequences of VEGF-C activation, on the other hand, are more difficult to predict because activated VEGF-C does simultaneously both good and bad: On the one hand, it facilitates metastasis. On the other hand, it enables an enhanced immune response against the tumour. Interesting research lies ahead. Read more in our review: https://doi.org/10.3390/ijms222413545

3. Swiss Lymphsymposium

Fri, 17 Sep 2021 00:00:00 +0000

The English translation of the German talk (slides and abstract) is available from here: https://doi.org/10.5281/zenodo.6034307 . The 3. Swiss Lymphsymposium took place on September 4th in Zürich. It is sponsored by Juzo , a producer of garments for complex physical decongestive therapy (CPDT), which is the main therapeutic option for lymphedema therapy. CDT cannot heal but it keeps the symptoms under control. I really liked the talk by Prof. Erich Brenner, since it nicely addressed the issue of blind-ended “lymphatic capillaries”, which, with some exceptions, do probably rarely exist in the steady-state adult human anatomy. I had discussed this previously with others such as Johannes Grünzig ( https://doi.org/10.1016/j.aanat.2018.08.004 ), who specifically looked at the shape of the initial lymphatics in the eye. I was asking Erich where the concept of blind-ended capillaries originates from and it seems to have its origins in early drawings from German physiologists. As a matter of fact, I myself have been perpetuating the blind-ended initial lymphatics in my schematic drawings, e.g. here , without paying much attention to the issue. As a defense, I can argue that the low magnification shows only the larger collectors and the high magnification suffers from the narrow depth of field. In fact, the depth of field can indeed give sometimes the impression of blind endings, while in reality, the vessel might simply make a turn. However, I have also seen convincing images with blind-ended initial lymphatics. From a functional perspective, which geometry would be the better choice? I guess nature is good at optimizing structures…Of course many of us molecular scientists have seen real blind-ended lymphatics. Obviously, during development and other situations of lymphatic expansion (wound healing, VEGF-C application), such lymphatic blind-ended sprouts do exist. We often also look at lymphatics in places where such finger-like structures do de-facto persist throughout adulthood (i.e. in the villi of the digestive tract). However, here the constant high supply of VEGF-C is likely involved in maintaining these unusual structures ( https://doi.org/10.15252/emmm.201505731 ).In my talk, I was addressing the current status of therapeutic lymphangiogenesis. Using VEGF-C, we can induce the growth of new lymphatic structures, but the current gene therapy (Lymfactin) is only able to deliver a short burst of VEGF-C because the delivery vector (an adenovirus) is rapidly inactivated by the immune system. Hence, the clinical studies were well chosen: to jump-start the integration of lymph node transplants into the local lymphatic network. But given this relatively narrow indication, the business decision by Herantis Pharma to focus on its neurodegenerative pipeline and to discontinue the Lymfactin development is even understandable. IMHO, we would need molecular nudging in order to make an impact in most human lymphedema conditions, which are - for the most part - chronic. A low-level, distributed stimulation of lymphatic collector contraction would need to be combined with a higher capacity network. VEGF-C could do the trick, but at this moment, we do not have any technology that could reliably deliver such a molecular nudge for a long time, although there are many ideas on how one could pull this off.The Ketoprofen/Bestatin trials have shown, that there is a big difference between acute and chronic lymphedema. The mouse lymphedema, which was treated surprisingly effectively with ketoprofen, is very different from human chronic lymphedema. One thing we certainly need is better animal models for chronic lymphedema. Interestingly, chronic lymphedema is a common problem in horses.This seems to be an old hat for those familiar with horses, but for me this was new: The same conservative standard treatment is used for horse and human lymphedema: complex physical decongestion therapy. I was just surprised that there are enough equine patients in order for some researchers and practitioners to specialize in the lymphedema treatment for horses: https://www.equicrown.de or https://horsephysio.at/uber-uns.htmlFrom a scientific point of view, this type of edema is likely much more similar to human lymphedema than all the mouse models that we have: it’s a big animal with high hydrostatic pressure in the legs and it’s a chronic condition. I am wondering what are the molecular causes for horse lymphedema, and whether this problem was caused by domestication/breeding, i.e. whether wild horses/zebras have also lymphedema? I would love to talk to somebody who knows something about this!Thanks to Sonja Eham & Dr. Michael Oberlin for the additional info concerning horse lymphedema, and Sonja Eham & Dace Zanker for an impeccable organization. I guess I should immediately start to clone horse VEGF-C…

Searching for a lymphedema drug

Wed, 11 Aug 2021 00:00:00 +0000

More than 20 years ago, I cloned the VEGF-C cDNA into an adenovirus shuttle vector. Even though we had the vectors for the AdEasy system from Bert Vogelstein’s lab to make adenoviruses in-house, we preferred to team up with gene therapy expert Seppo Ylä-Herttuala to make the first adenovirus with VEGF-C cargo (AdVEGF-C). This and other VEGF-C-expressing adenoviruses have been used by Seppo and us in several preclinical studies to show that VEGF-C can be successfully used to treat the underlying cause of certain types of lymphedema.In 2018, Herantis Pharma started Phase 1 clinical trials with AdVEGF-C, which was branded under the name Lymfactin. After Eiger Biopharmaceuticals ’ Phase-2-trials with bestatin failed to show any effect on lymphedema, Lymfactin was the only drug in clinical trials that was aimed at lymphedema. This spring, Herantis announced that it is discontinuing the clinical trials with Lymfactin in order to focus on their neurodegenerative ( CDNF ) drug pipeline. On top of this bummer came the news that the assignment of patients for the phase-2 trial had been non-random and that the Phase-2 results are therefore inconclusive . This is bad news for lymphedema patients just when gene therapy, on the whole, is making a comeback after an almost two-decade-long hiatus.What is the way forward? Even though the small molecule drug bestatin was shown to increase VEGFR-3 expression and activation , it was never a pro-lymphangiogenic therapy. The mouse experiments had shown clearly that it merely supports the endogenous lymphatic repair that is naturally kicking in after acute lymphatic damage. It specifically counteracts too high leukotriene B4 levels, which inhibit lymphangiogenesis, but it does not carry any own lymphangiogenic signal.The strategy to inhibit an inhibitor was also used in mouse studies that were published today in Science Signaling by Kataru et al.: Kataru et al. Kataru et al. used genetic modification of lymphatic endothelial cells to block PTEN, an intracellular inhibitor of VEGFR-3 signalling. The results are convincing: Lymphangiogenesis without any of the drawbacks that are inevitably associated with growth factor therapy, such as having too high growth factor concentrations at the site of delivery, which can lead to vessel leakiness and other unwanted responses. Small molecule PTEN inhibitors do exist, but they are pretty toxic. If a reasonably non-toxic PTEN-inhibitory compound could be found, all that is left is to specifically target it to lymphatic endothelial cells. However, neither finding nor targeting are easy tasks, although there are enough ideas that could be followed if funding was available. Read more about this topic in our opinion piece about searching for a lymphedema drug in Science Signaling: doi-link , e-print link for those who have no access to the full text.

MDPI peer review reviewed

Wed, 24 Feb 2021 00:00:00 +0000

Finally, our most recent review got published in the journal Biology. For my taste, its title is too long: Proteolytic Cleavages in the VEGF Family: Generating Diversity Among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs . On top of this, the title contains an abbreviation: VEGF.Most publishers are in for the moneyThis is the first time we published with MDPI . Although the criticism of MDPI has not entirely gone away after its 2015 vindication from Beall’s List , the critique is now mostly centered around the accusation that MDPI is after the money and not the quality. That said, most publishers are in it for the money. Especially the stock-market listed publishers are by law forced to be in it for the money: Elsevier, John Wiley & Sons, etc. And many others such as Springer Nature are desperately trying to become also a member of the stock-market listed club. We as scientists could probably use a little bit of this attitude because we are naturally bad at making money (we can generate knowledge, but not revenues).Concerns over review qualityAdditionally, MDPI’s review process has been criticized as being not very rigorous. What was our experience? Our paper was apparently scrutinized by four reviewers and you can read the reviewers’ comments here: https://www.mdpi.com/2079-7737/10/2/167/review_report .**How did we experience the reviewers’ quality of feedback?**Three out of the four reviewers gave real feedback. Reviewer 3 could be - for all what matters - replaced by Grammarly.com or the Microsoft Word spell checker. Reviewer 2 focuses also almost entirely on style and presentation. Don’t get me wrong: Good style and presentation are very important! But, first of all, let’s get the science right! The remaining two reviewers were apparently not extremely familiar with the research topic vascular biology. This agrees with my own experience, that I often get requests from MPDI journals to review papers outside or only tangential to my area of expertise (which I immediately reject since I anyway have too many papers to review).You could argue in favor of MDPI, that our manuscript was already quite good when we first submitted it. But please: we cobbled this together in a hurry during the month of December and I know that there are still quite a few errors (which we realized a few minutes after the paper was published).We wanted to try an Open Review, but failedIt strikes me that we had opted for open review (i.e. only to use reviewers that were agreeing to publish their identity together with their reviews). However, none of our reviewers revealed their identity. There is probably some fine print somewhere that says that the editor can override this choice when no reviewers are found that agree to give up their anonymity. To a certain extent, I can feel the editor’s pain. It is difficult enough to find good peer reviewers in the first place, because - despite many attempts for a change - reviewing manuscripts is not rewarded in the current scientific system. Is it fast? Imho, some of it was too fastThe review process was fast. The revisions were even faster. And the publishing was much too fast. I was terrified when I saw that we might not get a second set of proofs. The first proofs had to be modified extensively because the layout had changed the image placement. As a consequence, almost all the references needed renumbering. Moreover, during the proof generation, some parts of the figure legends got mistaken as body text. Therefore we had to shift large portions of text around during the proofing. And if you ever have used Word, you know that this is nothing to be excited about. At least, MS Word doesn’t crash anymore as it used to do in the old days. Back then, pushing the Crtl-S key combo after every minute of editing was outsourced from the brain to the spinal cord. But also this time, Word did not disappoint us by introducing unwanted formatting changes that were impossible to undo.None of us managed to have even a look at the second proofs this Monday before the paper went online, after which the link to the second proofs expired. We have lots of other things to do: prepare lectures, participate in faculty meetings, take care of students, and - last but not least - we occasionally also like to do some research. Fast publishing is not a virtue in itself. But it certainly helps to keep the expenses in check.**After the game is before the game.**And this time it’s not a review, but original research and we will choose another publisher. The experience was definitely not a catastrophe, but I can clearly see that such an over-streamlined process can go wrong once in while with less scrupulous authors. And there are many examples (see the Wikipedia entry ).For those interested, here is the link to the translation of the Norwegian article discussing the MDPI quality issue.**UPDATE (15.01.2022)*After this experience, a scientific analysis of MDPI journals was performed, looking at self-citations, citation cartels, special issues, APC charges, and review- and acceptance times: https://doi.org/10.1093/reseval/rvab020 . I only became aware of this article more than half a year after its publication. The take-home message of it is that MDPI , as well as the publisher OMICS Interntional , engage in editorial behaviours that fall under the umbrella of predatory practices. At the same time, their operation “has reached such a level of sophistication that they totally or partially comply with the formal criteria that serve to differentiate between predatory and legitimate journals”. The authors of this analysis use the term “non-evident/hidden predatory publisher”.At the same time, many legitimate and respected scientists are working on the Editorial Boards of MDPI journals. I personally know quite a few. As always, the truth is not black or white but some shade of grey. Besides, this article was published by the reputable publisher Oxford University Press , which could be interpreted as a conflict of interest. *

Preprint and Open Review

Mon, 18 Jan 2021 00:00:00 +0000

In February 2020, Henry Kwok from the University of Macau asked me whether I want to contribute to an upcoming special issue in the journal Biology*. He was guest editing this special issue on the topic of Proteases — From Basic Structure to Function to Drug Design as Targeted Therapy. The topic is exactly what we are researching at the moment: whether we can target the lymphangiogenic growth factor VEGF-C via its activating proteases. So I tentatively agreed to contribute a review on the activation of VEGFs. We decided for the first time to simultaneously make the manuscript available as a preprint AND to ask for open review. Open review means that the reviewers’ comments and our rebuttal will be published together with the article if the article is accepted.

Review published in Duodecim: Lymphatics and the eye

Fri, 28 Aug 2020 00:00:00 +0000

English is overwhelmingly the number one language in science. Nevertheless, sometimes there is a need to target audiences different from academic researchers. In Finland, the bi-weekly Duodecim is arguably the medical journal with the biggest reach among domestic medical professionals. Hence, the idea for a Finnish language review was born. Viewed from three different angles (from the laboratories of Sirpa Loukovaara, Kaisa Lehti, and Michael Jeltsch), we are looking at proliferative diabetic retinopathy (PDR), which is an eye complication that develops slowly over decades in diabetic patients and which is still a major cause of blindness. The treatment of PDR is often less successful than it potentially could be. Importantly, we present also advances in PDR research, from which new ideas might emerge of how to improve current treatment regimens.The original Finnish language version of the review just went online: https://www.duodecimlehti.fi/lehti/2020/16/duo15739 . An English translation is available from Zenodo: https://doi.org/10.5281/zenodo.4005517 .

VEGF-C protects blood cell production

Fri, 28 Aug 2020 00:00:00 +0000

Vascular endothelial growth factor-C (VEGF-C) has been originally described as the primary growth factor for the lymphatic system. And not surprisingly, a constitutive inactivation of both VEGF-C gene alleles in mice is lethal.However, over the years, researchers have uncovered additional functions of VEGF-C. In 2016, it was shown that VEGF-C is necessary for the production of red blood cells (erythropoiesis) in the fetal liver. During embryonic development, the production site of red blood cells shifts twice: First from the yolk sac to the liver (in humans between the 3. and 4. month) and then, three months later, from the liver to the bone marrow, where it stays for the rest of the life. Vegfc appeared essential for the mobilization, maturation, and enucleation of primitive erythroblasts. When Vegfc was deleted on embryonic day 7.5 (E7.5), the liver colonization by erythro-myeloid progenitors and the macrophage/erythroid expansion was defective ( https://doi.org/10.1182/blood-2015-12-687970 ).Some, but not all of the effect was due to the VEGF-C that was produced by the hematopoietic cells themselves, which is not surprising since several blood cells are known to produce or contain VEGF-C (e.g. macrophages, platelets). In the 2016 paper, adult hematopoiesis appeared unaffected when VEGF-C was deleted in 8 week old mice. Also when erythropoiesis was upregulated by phenylhydrazine (PHZ)-stimulated anemia or when the bone marrow hematopoiesis was abrogated with fluorouracil (5-FU), no major changes had been seen. However, in the new paper, we show that VEGF-C does play an important role in the bone marrow recovery from radiation damage, and that it also is able to pro-actively protect the bone marrow when administered before the radiation damage occurs. The effect was partly due to bone marrow endothelial cells and LepR+ stromal cells, which, when stimulated with VEGF-C, produced factors favorable for the regeneration of hematopoietic stem cells ( https://doi.org/10.1182/blood.2020005699 ). However, the effect on LepR+ cells was likely indirect as they do not express receptors of VEGF-C. Considering that previous data show expression of VEGFR-2 on hematopoietic stem cells ( https://doi.org/10.1038/nature00821 ), and avian VEGFR-2 and-3 during in developmental endothelial/hematopoietic differentiation ( https://www.pnas.org/content/94/10/5141 and http://dev.biologists.org/content/125/4/743 ), also a direct effect of VEGF-C cannot imho be excluded although it was not analyzed.

Dr. Sawan K. Jha: Mechanism of VEGF-C Activation […]

Mon, 01 Jun 2020 00:00:00 +0000

My first Ph.D. mentee successfully defended his thesis on the topic Mechanism of VEGF-C Activation and Effect on Lymphatic Growth and Regeneration . Due to the COVID-19 situation, we organized the event remotely and used the Zoom virtual meeting software. The opponent was Prof. Jonathan Sleeman from the University of Heidelberg. Both the defendant and the opponent did a fantastic job, and the discussion brought to light several new directions for future research, which I had not been thinking about before. VEGF-C is a tricky protein and I am sure it still holds some surprises for the diligent researcher. Unfortunately, there was no reception, no dinner, and no karonkka (after-dinner graduation party), but we are planning to have a party later this year when the COVID-19 situation permits!

Lymphatics and the eye

Wed, 12 Feb 2020 00:00:00 +0000

Our shared review about the eye lymphatics has been accepted for publication by Duodecim . In addition to review our current understanding about the eye lymphatics, it focuses on proliferative diabetic retinopathy (PDR). PDR is the advanced stage of diabetic retinopathy, which is one of the slowly developing complications of diabetes and which can result in blindness.It has been known for a long time that damage to the blood vessels in the retina is a central event in the disease development. Antiangiogenic therapy, targeting the major angiogenic growth factor VEGF-A, is a cornerstone of the therapy. However, the recent discovery of lymphatic-type vessels in the disease indicates, that it might be helpful to target also the lymphatic growth factors VEGF-C and VEGF-D. This is my first contribution to an article that is written in Finnish. While I even wrote some of the sentences in Finnish myself, big thanks go to Ani and Timo for weeding out the mistakes. However, my take-home message for similar future endeavors (i.e. writing with a team where key members are not very proficient in the target language) is that one should write everything first in English and then have it translated into the target language. If common languages are concerned, the best tool for the automated translation of scientific articles is DeepL . However, DeepL does not know Finnish, and adding Finnish is certainly not high on the developer’s priority list…

Lymphologie 2019

Sat, 12 Oct 2019 00:00:00 +0000

A week ago, I visited Germany to participate in the Lymphologie 2019 conference, which took place in Bad Krozingen near Freiburg.The conference is jointly organized every two years by the DGL ( Deutsche Gesellschaft für Lymphologie ) and the GDL ( Gesellschaft Deutschsprachiger Lymphologen ). The meeting is overall very hands-on and clinically oriented with many workshops and practical advice. Therefore, it’s highly recommended for practitioners who are able to understand German. However, there is also a “basic science” track, and the organizers always manage to recruit some decent scientists for this track (see here: https://www.lymphologie-kongress.de/programm/samstag-03-10-15/) . Notably, the talks are delivered in German, which doesn’t make the recruiting task easier. Lymphologists in Germany continue to play a leading role in the treatment of lymphedema (and recently lipedema) with uniquely specialized experts and facilities ( Földiklinik ), but English has become the language of biomedical research also in Germany. However, there is still a need for dissemination of research results in German language and that’s why I contribute occasionally to the German-language journal “Lymphologie in Forschung und Praxis”.

ISK 2019

Thu, 10 Oct 2019 00:00:00 +0000

The International Symposium on Kallikreins and Kallikrein-related Peptidases (ISK) took place on September 25.-27. in Prague. Being not from the kallikrein-field, I learned a lot. E.g. I was not aware that KLK4 can activate plasminogen (a fact that might explain some of our early, inconsistent results where KLK4 occasionally seemed to weakly activate VEGF-C in cell culture). Not surprisingly, many participants were interested in our findings that KLK3/PSA can activate the growth factors VEGF-C and VEGF-D, both of which are implicated in cancer progression, notably in metastasis. They confirmed that there is not very much research on the effect of KLK3/PSA mutations on human fertility, but I am sure that someone is going to look at that.Even though it is considered more prestigious to deliver a speech than to present a poster, I have to reconsider and perhaps will present next time a poster. What I would prefer most: talking AND presenting and poster. Why do so few conferences offer this possibility? What depth can you delve into if you have only 15 minutes on stage? Has the attention span of conference participants really decreased over the recent decades due to Facebook, Youtube and Instagram? Maybe: https://www.telegraph.co.uk/science/2016/03/12/humans-have-shorter-attention-span-than-goldfish-thanks-to-smart/The atmosphere at the conference was really friendly and cooperative, perhaps also owing to the relatively small number of participants. If we really should extend our excursion into the KLK-field, I have many experts to turn to for help. I also met some researchers from the Charles University of Prague, who are doing lymphatic research and it looks like we can help each other out with our specific experimental possibilities. All in all, a very successful trip. Excluding the Lufthansa flight back home, which arrived so late for transit in Frankfurt that I did not manage to do shopping there on my way back as I had originally planned (many shops in Germany do close at 5 pm).

Re-purposing the growth factor VEGF-C

Sat, 22 Jun 2019 00:00:00 +0000

An eLIFE digest features our recent publication about VEGF-C ( https://elifesciences.org/digests/44478/re-purposing-the-growth-factor-vegf-c ). Even though our research did not deeply delve into the function of VEGF-C during reproduction, the reviewers comments and our answers (under the “Author response” heading) give more insight than the publication itself. We did not include the sperm motility data in the manuscript. Although sometimes stunning in its magnitude, we did not always measure increased sperm motility in response to active VEGF-C. As is common knowledge, sperm as a biological sample is of highly fluctuating consistency and quality. Interestingly, a paper in eLIFE published two years ago gives some additional insight in what we might be dealing with: Sperm competition risk drives rapid ejaculate adjustments mediated by seminal fluid . This paper shows that the swimming speed of sperm is rapidly regulated by males depending on the social situation (presence of a female or a male competitor). Imho, such factors seem to be almost impossible to control when dealing with human samples…However, the title ambiguously also refers to cancer. Based on our data, we speculate that VEGF-C can be repurposed from being lymphangiogenic to being angiogenic, and further, to be metastasis-promoting.

Lymphologische (Grundlagen-)Forschung: wie funktioniert das?

Wed, 29 May 2019 00:00:00 +0000

Vortrag für den 43. Jahreskongress der Deutschen Desellschaft für Lymphologie

PD Dr. Michael Jeltsch Universität Helsinki & Wihuri-Forschungsinstitut Haartmaninkatu 8 FIN-00290 Helsinki, Finnland michael@jeltsch.org

KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D

Sat, 18 May 2019 00:00:00 +0000

Prostate-specific antigen (PSA) is well known - at least among older males - as a prostate cancer marker, but few people know its physiological function: Sperm cells are trapped in fresh ejaculate, which has a jelly-like consistence. In order to release the sperm cells, the ejaculate needs to be liquefied and precisely this liquefaction is the task of PSA.Also surprising for many people is the fact, that scientists still do not know why high PSA levels are associated with prostate cancer. In our latest research published yesterday in eLIFE , we have made a big step ahead in understanding the role of PSA in both reproductive and cancer biology.It appears that PSA (aka as kallikrein-related peptidase 3 - KLK3) and another enzyme called cathepsin D can activate two growth factors which have been implicated in cancer progression: VEGF-C and VEGF-D . These growth factors do likely contribute to tumor angiogenesis and tumor lymphangiogenesis. By inducing angiogenesis - the growth of blood vessels - the tumor ensures its own supply with nutrients and oxygen. Such blood supply is necessary for a tumor to grow beyond the size of a few millimeters. Likewise, tumor lymphangiogenesis happens when the tumor induces the growth of lymphatic vessels and it is tightly linked to the lymphatic spread (metastasis) of the tumor.Both VEGF-C and VEGF-D are produced as inactive precursors (pro-VEGF-C, pro-VEGF-D) and need to be activated in order to induce the growth of blood or lymphatic vessels. With ADAMTS3 , we have identified the enzyme that activates VEGF-C during embryonic development - which also requires vessel growth - in 2014 ( Jeltsch et al. ). However, it remained unclear whether the same enzyme is responsible also for pathological vessel growth. Now it seems likely that patholigical vessel growth uses different enzymes and PSA and cathepsin D have become prime suspects. Our next experiments will test whether we can slow down or halt cancer growth by blocking these enzymes.

1000+ citations

Wed, 15 May 2019 00:00:00 +0000

The first among my publications to brake the 1000 citations-barrier was Gerhardt et al. 2003 . With the “tip cell concept”, it set a paradigm for vascular biology research: Not all endothelial cells are equal and the tip cell is a specialized cell that marks the forefront of the angiogenic sprout. However, my contribution was limited (number 7 out of 11 authors): I produced most of the proteins that were needed for the study. This spring, Jeltsch et al. 1997 crossed the first time the 1000-citation mark. The paper describes a mouse, that overexpresses VEGF-C in the skin. It is the first ever in-vivo demonstration of a lymphangiogenic growth factor. Although not setting any paradigm, it marks the start of the molecular era in lymphatic research . What percentage of papers achieve 1000+ citations? That differs between disciplines, but e.g. according to https://en.wikipedia.org/wiki/Citation_impact on average it is less than 1 in 4000. Compare this to the average paper, which receives 7.8 citations. And even this average is heavily influenced by a few highly-cited papers ( similar to the Impact Factor ). The median number of citations is 4, meaning that about half of all papers have less than 4 citations (see here ).

International Vascular Biology Meeting 2018 organizational feedback

Wed, 20 Jun 2018 00:00:00 +0000

As member of the local organizing committee for the IVBM 2018 , I was asking conference participants for direct feedback. I received lots of praise, which I do not want to iterate here. If we are ever going to organize a large international conference again, here are the things that we should do differently next time. Maybe this list can also help other first-time organizers of large, international conferences. If this list gives you the impression that the conference was badly organized, you would be mistaken! All the important stuff worked smoothly and some of the issues below were solved before any of the participants noticed. However, there is always room for improvement of the details! And - as always - some of the issues were out of our control as we had outsourced some of the work, most notably to Confedent International . And some decisions were a compromise between the optimal and what the conference budget could accommodate. I also encourage you to contact me if you want to add something to this list; it could make things better in the future!

Minireview about key molecules in lymphatic development, function, and identification

Fri, 08 Jun 2018 00:00:00 +0000

Erich Brenner asked us more than a year ago whether we could contribute to the special issue about human lymph vessels he was editing for Annals of Anatomy. We agreed that we might be able to contribute a minireview. In the beginning, I was also hesitating, because Annals of Anatomy is not per se an open access journal. However, our university has meanwhile started to cover the article processing charges (APCs) for several publishers (including the biggest scientific publisher on this planet - Elsevier ) to make articles open access . Thus, everybody can not only read the article already now, but also share, copy and redistribute it, remix, transform, and build upon it for any purpose, even for commercial purposes as long as we - the original authors - are credited.The target audience is not the lymphatic research community, but outsiders, who need a first, very brief introduction to the molecules that are most central to the molecular biology of the lymphatic system. The selection is clearly biased by our own research history. Please write us an angry e-mail if we did not include your pet protein! If you convince us that your pet protein is central to lymphatic development or function, we’ll include it in our next review!

IVBM 2018 & 2020 (poster, talk, and virtual poster walk through)

Wed, 06 Jun 2018 00:00:00 +0000

IVBM 2018The International Vascular Biology Conference 2018 in the Finlandia Hall in Helsinki has been a big success so far. We received lots of positive feedback for the organization from the participants. Also my talk (“Everything You Always Wanted to Know About the Proteolytic Processing of VEGF-C”) and my poster received good attention.Below the poster as a PDF download.IVBM 2020The IVBM 2020 in Seoul, South Korea, moved completely online. Unfortunately, some talks are only available for a very short time (one day), and I missed already a few of those. A physical conference has the advantage that it makes sure that you can pay full attention to the event. An online event has to compete with many other issues that are trying to grab your attention.

VEGF-C Review in Frontiers in Bioengineering and Biotechnology

Mon, 12 Feb 2018 00:00:00 +0000

The editors of Frontiers in Bioengineering and Biotechnology, section Tissue Engineering and Regenerative Medicine (Andrea Banfi, Wolfgang Holnthoner, Mikaël M. Martino and Seppo Ylä-Herttuala) asked us to contribute to the research topic Vascularization for Regenerative Medicine. We wrote a small review about VEGF-C, which specifically addresses the molecular biology of VEGF-C in relationship to regenerative medicine, i.e., (re)growing lymphatic vessels in vitro or in vivo.You can get it from the publisher directly https://www.frontiersin.org/articles/10.3389/fbioe.2018.00007/full or from here . **UPDATE (April 1, 2023):**The question of whether Frontiers Media is a predatory publisher did not even cross our minds when we were asked to contribute with a review. I know the guest editors of this Research Topic and can vouch for their scientific integrity. However, the journal has recently ended up on the list of predatory journals ( https://predatoryreports.org/news/f/list-of-all-frontiers-media-predatory-journals ), and the issues are discussed here in detail. Our review has meanwhile gathered:

20th International Vascular Biology Meeting in Helsinki, Finland

Mon, 27 Nov 2017 00:00:00 +0000

The 20th International Vascular Biology Meeting 2018 (IVBM2018) will take place in Helsinki, Finland on June 3-7. Registration has opened ( https://b3p.it.helsinki.fi/IVBM/ ) and I hope to see you in Helsinki in June! I have been living here in Helsinki for about 20 years, hence feel free to ask me anything! If I cannot answer, I at least know who knows the answer.

Lymphologica 2017

Wed, 01 Nov 2017 00:00:00 +0000

On the Lymphologica 2017 (Lymphologie 2017) congress in Bad Soden (Oct. 5-7, Frankfurt, Germany), I presented an introduction to the molecular biology of VEGF-C and how mutations in the genes of the VEGF-C/VEGFR-3 signaling axis can cause or contribute to hereditary lymphedema. The talk was targeted at healthcare practitioners who work in the lymphology field. A mini-review based on this talk was published in Vasomed and was available online , but has meanwhile disappeared. You can download the presentation slides and the English translation of the mini-review via the download link below.

Essentials facts about VEGF-C in lymphology

Fri, 05 May 2017 00:00:00 +0000

Essentials facts about VEGF-C in lymphology

Dr. Michael Jeltsch, Adjunct Professor, University of Helsinki & Wihuri Research Institute, Finland, michael@jeltsch.org

Vascular endothelial growth factor C (VEGF-C) is essential for the development and growth of the lymphatic vasculature. Together with VEGF-D, it forms the lymphatic subgroup within the VEGF family of growth factors, whose other members (PlGF, VEGF/VEGF-A, VEGF-B) are primarily responsible for the growth and function of blood vessels. VEGF-C was discovered as a ligand of the tyrosine kinase receptor VEGFR-3 (1) and its specific effect on lymph vessels was first described in 1997 (2,3). About one-third of hereditary lymphedema cases in humans result from mutations in genes involved in VEGF-C signaling (4). The complete absence of VEGF-C leads to death during embryogenesis (5). Likely for this reason, clinical cases of hereditary lymphedema are characterised by a partial inactivation of the signal transduction. VEGFR-3 (6) is affected in most cases, but mutations of the hereditary lymphedema are described or suspected for all components of the VEGF-C signal transduction described below, partly within a multifactorial inheritance.

A Very Short History of Antiangiogenic Tumor Treatment

Mon, 24 Apr 2017 00:00:00 +0000

I covered the antiangiogenic tumor treatment topic in the Cancerbio Summer School (CBSS) 2017. As a review I recommended the following: Weis SM, Cheresh DA. Tumor angiogenesis: molecular pathways and therapeutic targets. 2011. Nature Medicine 17:1359-70. http://www.nature.com/nm/journal/v17/n11/pdf/nm.2537.pdf

Angiogenesis landmark publications

Thu, 09 Mar 2017 00:00:00 +0000

According to Nature, our Science paper from 1997 is a landmark paper for the angiogenesis field: *“A paper establishing the role of VEGF-C and VEGF-R3 signaling in lymphangiogenesis. A new field is born."*The collection of landmark papers for the angiogenesis field from the last 80 years ( http://www.nature.com/focus/angiogenesis/classics/vegf.html ) was published first in 2003 and unfortunately has not been updated to include later seminal studies. However, until today, most of these 86 papers are still must-reads for every PhD student in the angogenesis field.

Science good, coffee bad

Thu, 26 Jan 2017 00:00:00 +0000

Last week I took part the Vascular Cell Biology Gordon Research Conference in Ventura (California). My two previous Gordon Conferences (2001 Rhode Island, 2014 Lucca/Italy) were outstanding and also this one did not disappoint.Even though there were many European researchers (19%), the US made up for 69% of the participants (Asia 6%, rest of the Amerikas 5%). This is probably a good representation of where the cutting edge research in vascular biology happens. Makes me wonder why the coffee in the US is as bad as it is (my bias got confirmed again). It cannot be explained by the lack of scientific expertise.Gordon conferences are designed to promote the exchange of unpublished data and hence I am not writing anything about the science. One exception: There are clinical trials to treat lymphedema with leukotriene B4 inhibitors ), but this is already public knowledge and the mouse studies are mostly published ( http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008380) . So no secrets leaked here… I myself presented a poster about the continued CCBE1 story that is currently under review and some preliminary data about additional VEGF-C activating enzymes.Obviously, the outcome of the presidential elections was a popular topic during lunch and dinner conversations especially as it relates to science funding and science policy. Opinions ranged from “We have no clue what to expect” to “Be afraid. Be very afraid.” I personally enjoyed about 8 hours of Trump presidency since my return flight from Los Angeles to Munich left last Friday at a quarter past five in the afternoon.In the free afternoons, I tried to catch the America-exclusive Taurus Pokémon for my daughter Milena. Sadly, the conference location was almost entirely devoid of poke stops and therfore I was chronically short of poke balls. Insiders told me that Santa Monica beach is the place to go to in order to catch Pokémons. I actually planned to go there Friday morning, but it was raining cats and dogs and so I tried my luck at the airport and about an hour before departure I finally managed to catch a Taurus and another one just before boarding the plane. So all in all a very successful conference journey!

RPU Seminar 2016

Fri, 24 Jun 2016 00:00:00 +0000

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Centrifugal and centripetal embryonic lymphatic development

Tue, 19 Jan 2016 00:00:00 +0000

Since the beginning of last century, researchers have been arguing about the embryonic origin of the lymphatic system. Some claimed that it is in its entirety an outgrowth from blood vessels (so-called centrifugal hypothesis with Florence Sabin and Louis-Antoine Ranvier as early proponents, this mechanism of growth is called “lymphangiogenesis”). Others maintained the view that the lymph vessels do form newly from precursor cells in the mesenchyme (so-called centripetal hypothesis with George Huntington and Charles McClure as early proponents, this mechanism is called “lymphvasculogenesis”). This controversy has been going on for more than a century and several published studies within the last years show, that the truth lies somewhere in between both views. Such synthesis had been proposed already in 1932 by van der Jagt. Kenny Mattonet and myself wrote a short update on the topic and you can read the English version or the German original .

This year's Nobel prizes

Mon, 12 Oct 2015 00:00:00 +0000

Three of this year’s nobel prizes were given for topics we work on: The prize in Medicine was shared by Youyou Tu and William Campbell/Satoshi Ōmura. Campbell and Ōmura received their share for the development of an anti-parasite drug that is effective against roundworms (nematodes), which are the cause of river blindness, lymphatic filariasis and a few other diseases. Nematodes, that cause lymphatic filariasis (like Brugia malayi) are living in the lymphatic system. Many nematodes do express a VEGF-C-like molecule, but the function of this parasite-VEGF-C for the nematode’s life cycle has never been looked at.The prize in Chemistry was shared by Tomas Lindahl, Paul Modrich and Aziz Sancar for their mechanistic studies of DNA repair. We are right now experimenting with such mechanisms, especially the cytidine deamination, which we exploit in order to generate mutations on demand. When cytidine is converted into uracil (which can happen spontaneously or mediated by an enzyme), the enzyme Uracil-DNA glycosylase (UNG) removes the uracil base. Then another enzyme (apurinic/apyrimidinic endonuclease) cleaves the backbone 5’ to the abasic site and DNA polymerase beta excises the abasic sugar phosphate residue and inserts a cytosine thus repairing the damage.The third prize is the one in Economic Sciences, which went to Angus Deaton. “He pioneered the analysis of individual dynamic consumption behavior under idiosyncratic uncertainty and liquidity constraints.” (from the Advanced Information PDF by the Royal Academy. I freely translate: He researched how peoples ‘spending behaviour changes in the face of irregular and insufficient income. That describes quite well our lab’s financial situation and we indeed work on that issue, because science without money doesn’t work.

Erkrankungen des Lymphgefäßsystems (Diseases of the Lymphatic System)

Wed, 05 Aug 2015 00:00:00 +0000

The 6th edition of the the book Erkrankungen des Lymphgefäßsystems (Diseases of the Lymphatic System) is out. It’s a German language textbook, for which Kenny Mattonet, Jörg Wilting and myself wrote the fifth chapter (Genetic causes of primary lymphedema). Get it from here , since Amazon still sells the old, 5th edition. If you have a really good excuse why you should get one for free, mail me! I have a few copies.

Lymphangiogenesis in health and disease

Thu, 11 Jun 2015 00:00:00 +0000

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Best paper award

Fri, 01 May 2015 00:00:00 +0000

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![](/sites/]( http://www.med.helsinki.fi/english/news/2015/20150505_Jeltsch.html)We have won Circulation’s 2014 Best Paper Award in the category of Basic Science. Circulation is the leading cardiology journal and the organ of the American Heart Association . Already when we published the paper (titled [/files/files/Jeltsch%20et%20al.%20-%202014%20-%20CCBE1%20Enhances%20Lymphangiogenesis%20via%20A%20Disintegrin.pdf">“CCBE1 Enhances Lymphangiogenesis via A Disintegrin and Metalloprotease With Thrombospondin Motifs-3–Mediated Vascular Endothelial Growth Factor-C Activation”](/sites/<?php print $_SERVER[)), it was clear that it provided a major overhaul of our understanding of the VEGF-C growth factor and it got featured by Open Heart . The article manages to provide multiple new insights:

38. Annual Congress of the German Society for Lymphology

Sun, 05 Oct 2014 00:00:00 +0000

I participated in the 38th Congress of the German Lymphological Society ( http://www.dglymph.de/ ) in Halle (Saale). The conference was very refreshing and interesting: It was very different from the meetings I typically attend because it was focussed on the practical aspects of clinical and ambulant management of diseases that involve the lymphatics. Because my talk was an introductory lecture about lymphangiogenesis research, it did not contain any unpublished data and hence I make it available for download. However, the slides are in German and - depending on the target audience - might require some commentary. The talk is a chronological account of the important publications in the field of lymphangiogenesis research starting from about 20 years ago; heavily biased towards my own work and work in which I have been participating.

New Mechanisms of Lymphangiogenesis and Lymphedema

Fri, 26 Sep 2014 00:00:00 +0000

Here is the presentation that I could not give, because my schedule was too tight to allow for a 1 hour 20 minute delay. If you have questions concerning the talk, please ask via e-mail: michael@jeltsch.org.My Lufthansa flight LH855 from Helsinki to Frankfurt got delayed by 1 hour 20 minutes. Because I had only 1 hour 15 minutes to change my plane in Frankfurt on my way to the 40th Congress of the European Society of Lymphology in Genova/Italy, I did not even board the plane and rather canceled my talk. Because I have another appointment on Saturday in Germany, I had planned the return flight for Friday early morning and hence could not move my talk either. Next time I’ll be smarter.

From the molecular biological foundations to causal treatment options for diseases of the lymphatic system

Tue, 22 Jul 2014 00:00:00 +0000

PD Dr Michael Jeltsch, University of Helsinki, Finland

Research into the molecular basis of lymphangiogenesis in embryonic development and pathological processes has led to a rapid expansion of our knowledge (Krebs and Jeltsch 2013a, 2013b). The molecular biology era of lymphatic research began with the discovery of VEGF growth factors and their receptors 25 years ago. This review therefore focuses on these molecules.

We got featured by Circulation!

Mon, 12 May 2014 00:00:00 +0000

The molecular basis of Hennekam syndrome

Thu, 20 Feb 2014 00:00:00 +0000

Finally our CCBE1 manuscript is out! You can access it from the Circulation’s homepage . If your library does not have a subscription, just drop me an e-mail . It nicely complements the article by Le Guen et al. from Ben Hogan’s group in Development. While Le Guen and colleagues analyzed the interaction of CCBE1 with the VEGF-C/VEGFR-3 pathway mainly at the genetic level in zebrafish, we tried to describe the molecular details of the interaction using in vitro assays which we complement with in vivo mouse data. We describe that the primary lymphangiogenic factor VEGF-C is produced as an inactive precursor (pro-VEGF-C). Pro-VEGF-C (that is the 29/31-kDa-form) does bind to VEGFR-3 on endothelial cells, but is unable to activate it. Until now, the common wisdom was that pro-VEGF-C is only a less potent activator of VEGFR-3 than mature VEGF-C. In fact, it actually acts as a competitive inhibitor of mature VEGF-C. The task of CCBE1 is to assist the ADAMTS3 protease in cleaving cell-surface bound pro-VEGF-C and thus to localize the concentration of active VEGF-C. In hereditary diseases that are caused by mutations in CCBE1 ( Hennekam syndrome ), this activation of VEGF-C is impaired and causes lymphedema. Because of the importance of lymphatic vessels in many diseases, CCBE1 and ADAMTS3 are interesting drug targets. In cancer, for example, it would be a tremendous benefit if one could prevent the activation of VEGF-C and thus prevent VEGF-C-mediated metastasis.

SVS or lymphatic system?

Sun, 26 Jan 2014 00:00:00 +0000

In 2003, I wrote a review article about the lymphatic system , in which I briefly discuss the general setup of the lymphatics in different animals and I got the part about the lymphatic system in fishes wrong. Or at the very least it was incomplete.While mammals, birds, reptiles and amphibia are quite easily defined animal classes, there is no animal class “fishes”. Different ways exist to classify “fishes”, but at least three animal classes are needed to accommodate the living “fishes”: cartilaginous fishes, ray-finned bony fishes and lobe-finned fishes. Almost all research on the lymphatic system of fishes had been done on teleost fishes (one of three infraclasses of the ray-finned bony fishes). Teleostei comprise most of the living fishes including the mostly studied zebrafish (Danio rerio) . So everything that follows is about this infraclass (and hence might not apply to sharks and sturgeons to name just two non-teleost fishes).

Historic articles about the lymphatic system

Sat, 25 Jan 2014 00:00:00 +0000

Permission to self-archive

Tue, 21 Jan 2014 00:00:00 +0000

Thanks to Jörg Wilting , I finally received permission from the Deutsche Gesellschaft für Lymphologie (German Society for Lymphology ) to self-archive two review articles that I have been writing last year for the journal Lymphologie in Forschung ind Praxis . This is important, because otherwise, the impact sphere of the review would have been very limited. The first article discusses the molecular main players of lymphangiogenesis: VEGF-C and VEGF-D and their functions in embryonic lymphangiogenesis. The second article tries to summarize the roles that VEGF-C and VEGF-D play in diseases that are affecting the lymphatic system.

A Nobel Prize for angiogenesis research?

Sun, 27 Oct 2013 00:00:00 +0000

In 2008, during a dinner in Stockholm (when I participated in the Novo Nordisk Foundation 8th Annual Conference on Vascular Biology in Diabetes Complications) I proposed to Christer Betsholtz to award the Nobel Prize to the world-wide community of postdocs, which are the unsung heroes of today’s research. But the Statutes of the Nobel Foundation forbid to award the price to more than three people. However, statutes can be changed and the Nobel Foundation did exactly that 40 years ago when they stopped awarding the price to dead people. And in this changing world, less and less discoveries and inventions are made by individuals. But here’s my newest proposal, which adheres to the rule of maximally three: Kari Alitalo is probably the only Nobel Prize worthy researcher in the country where I work (Finland). Seriously: after Judah Folkman has passed away, there are not many options to award the prize to somebody from the angiogenesis field. Judah Folkman was the father of the hypothesis, that all tumors should be treatable by anti-angiogenesis ( Folkman J. Tumor Angiogenesis: Therapeutic Implications. New England Journal of Medicine. 1971;285(21):1182–6 ). The Nobel Prize committee missed that chance. And because the field has already significantly contributed to the treatment of cancer (and arguably will still contribute much), it is not so far off to think of a shared prize for the discoverers of the VEGFs. VEGF was discovered more or less independently by several research groups around 25 years ago, among them Napoleone Ferrara ’s and Harold Dvorak ’s. Most notably, Ferrara’s group at Genentech continued the research most successfully until today resulting in the first antiangiogenic cancer drug in 2004. While the discovery of VEGF and the resulting angiogenesis research was not dependent on any single lab, the lymphangiogenesis field was essentially single-handedly re-invented and brought into the molecular era by Kari Alitalo in the years following 1995 - after it had become senile and was lingering without any significant progress since the 1960s. A shared prize to Ferrara, Dvorak and Alitalo? There is an anti-VEGF-A cancer drug on the market and the only thing lacking is a successful anti- or pro-VEGF-C drug. Both are in clinical trials as of this writing ( anti-VEGF-C , pro-VEGF-C ).

Self Archiving and Open Access

Sun, 07 Jul 2013 00:00:00 +0000

I recently wrote a review article for the journal Lymphologie in Forschung ind Praxis . Its title was “Die lymphangiogenen Wachstumsfaktoren VEGF-C und VEGF-D” and it was the first paper I wrote in my mother tongue, German. This journal’s impact factor has been consistently below 1, which is not uncommon for non-English journals. However, in the big European countries like Germany, France and Italy, there are still many doctors who are not comfortable reading English. I though I’d help them out catching up on the latest in lymphatic research. Opening up access to science and visibility of science is all good, so I thought.Because my boss argued that it was a waste of time (I hope to prove him wrong - help me out here DLG !), I minimized the effort by engaging another knowledgeable German researcher at the University of Helsinki. Luckily I had already a draft when I was asked to write the review, even though I started to write it about two years ago and it was targeted for my website. When the article was published I received two physical reprints. When I tried linking to the online version of the article, I had to realize that it was behind a paywall . Because most publishers nowadays support self archiving , I asked the publisher about their policy. I presume that the publisher did not have any policy in place concerning self archiving, because they said they would agree to it, but I would have to get the green light from the board of directors of the DLG .I really hope to get this permission because this is the only way I can fulfill reprint request without hassle (yes I could copy the pages and send them by post (but aren’t we living in the 21st century?). If I won’t get the permission, one legal and easy way to distribute this article would be to put a pre-print version (i.e. the manuscript that I wrote) online. Luckily the copyrights of the publisher cover only the published version and not the pre-print versions. Others have done it this way (and they attached a list of the changes, that were made to make the pre-print version identical to the published version). This is a suboptimal solution, but maximizing accessibility and visibility. My University has a loose requirement to publish only in Open Access journals. However, exceptions to this policy of the University of Helsinki concerning Open Access are made on a regular basis, but they will get more and more difficult as the EU tightens their funding policy including the requirements for Open Access to research results . According to the EU’s interpretation, a journal could be considered Open Access if it allows for self archiving of the published article, self archiving being the second, “green” route to Open Access. The Academy of Finland (my main funding source) has a similar interpretation: “We further recommend that Academy-funded researchers publish their articles in open-access scientific journals, if there are online journals in the field in question that are at least of the same high quality as traditional subscription journals. The articles can also be saved in open-access electronic archives.” For employees of Helsinki University, self archiving is mandatory since 2010 .That makes sense to me: As a scientist I work with tax payers’ money; therefore all tax payers should have access to the results of my work. Even though I worked for this review only in my spare time, technically the requirements still apply as I used a computer, that was paid with tax payers’ money… Stay tuned and if you need the article now (and don’t want to wait for the DLG to decide), please e-mail me!

Lymphangiogenese-Regulation durch Wachstumsfaktoren

Thu, 19 Jan 2012 00:00:00 +0000

Alle Zellen unseres Körpers benötigen Sauerstoff und sie werden über das Blut damit versorgt. Deshalb ist das Gefässsystem das erste funktionsfähige Organ im wachsenden Embryo. Bevor das Herz seine Pumpfunktion aufnimmt, deckt der Embryo seinen Sauerstoffbedarf einzig durch Diffusion. Dies ist ihm allerdings nur bis zu einer Grösse von einigen Millimetern möglich.Tumoren haben das gleiche Problem, wenn sie eine ähnliche Grösse erreichen. Beide - der wachsende Embryo und die Krebsgeschwulst - können ihr Wachstum nur fortsetzen, wenn es ihnen gelingt, ein Gefässsystem zu bilden, das ihnen den benötigten Sauerstoff und die Nährstoffe bereitstellt.Das Krebswachstum ist also abhängig vom Wachstum und von der Neubildung von Blutgefässen. Andererseits gibt es aber auch Krankheiten, die von unzureichendem Blutgefäss-Wachstum charakterisiert werden. Bei der koronaren Herzkrankheit z. B. können die Blutgefässe dem Herzmuskel nicht genügend Sauerstoff liefern.Neben dem Herz-Kreislaufsystem gibt es noch ein anderes Gefässsystem: das Lymphgefässsystem. Es leitet überschüssige Gewebsflüssigkeit zuruck ins Blut und spielt eine wichtige Rolle in der körpereigenen Abwehr gegen Bakterien und Viren. Ähnlich dem Blutgefässsystem spielt das Lymphsystem eine wichtige Rolle in vielen Krankheiten. Lymphödem-Patienten z. B. leiden unter Schwellungen der Gliedmassen, weil entweder nicht aysreichend Lymphgefässe vorhanden sind oder die vorhandenen in ihrer Funktion eingeschränkt sind. Auch die Verbreitung von Krebs (Metastasierung) hängt eng mit dem Lymphsystem zusammen, weil Krebszellen die Lymphgefässe als Transportwege innerhalb des Körpers benutzten.

Introduction into lymphatic research

Thu, 20 Oct 2011 00:00:00 +0000

Lecture 1: The cardiovascular system vs. the lymphatic system: Anatomy and Physiology
Lecture 2: Molecular make-up of the lymphatic system
Lecture 3: The lymphatic system in disease
Lecture 4: Model organisms in lymphatic research , .tex file
Lecture 5: Fundamental techniques in lymphatic research
Lecture 6: Current questions in lymphatic research

Structure/function relationships within the VEGF/VEGF receptor families

Wed, 03 Aug 2011 00:00:00 +0000

The 8th International Duodecim symposium on “Endothelial growth factors in cancer and cardiovascular diseases” took place in the Vanajanlinna mansion from 9th to 11 June, 2011. It is just a bit more than 100 km from Helsinki and I did the trip by bicycle. This is the abstract for the poster I made for the meeting:

VEGF-C/VEGFR-2 complex structure took 13 years to solve

Wed, 03 Feb 2010 00:00:00 +0000

Finally our paper was accepted for publication in PNAS (downloadable also from here ). I started the project by making the first construct 13 years ago, but it went nowhere for the first 9 years due to insufficient concentration of efforts and a few unlucky choices in the experimental design. I opted for bacterial protein first, but although the refolding worked, it was very inefficient (Ala mutation and a smart trimming of N- and C-terminus. More…

Recombinant proteins

Fri, 25 Sep 2009 00:00:00 +0000

A dynamically updated list of proteins used to be here, but I shut down the communication to our lab’s database server due to security concerns.

Judah Folkman dies at age 74

Fri, 15 Feb 2008 00:00:00 +0000

Judah Folkman died of a heart attack at Denver airport on January 14. He was in transit to a conference in Vancouver. His importance for the field of vascular biology cannot be overstated; the web is full of his obituaries ( The Lancet , Nature , Cell just to link a few). I personally met him first when he acted as an opponent in Arja Kaipainen’s PhD thesis defense in spring 1997. Dear Nobel prize committee: You were again waiting too long.

Growth factor regulation of lymphangiogenesis

Sun, 06 Aug 2006 00:00:00 +0000

All cells in our body need oxygen and they receive it via the circulating blood. That’s why the vascular system is the first organ system to function in a developing embryo. Before the heart starts pumping, the embryo’s need for oxygen has to be met by diffusion alone. But diffusion is sufficient only until the embryo reaches a size of several millimetres. Tumours face the same problem, when reaching a similar size. Both the developing embryo and the solid tumor can only continue growing if they manage to establish a circulatory system that supplies them with oxygen and nutrients. While cancer depends on the pathological growth of blood vessels, other diseases are caused by insufficient vascular function. E.g. in cardiovascular disease the blood vessels cannot deliver enough oxygen to the heart muscle. Apart from the cardiovascular system there is another vascular system: the lymphatic system. It functions mainly in tissue drainage and immune defense against pathogens. Similar to the cardiovascular function, the lymphatic system plays an important role in several diseases. E.g. in lymphedema patients suffer from swollen limbs because lymphatic vessels are absent or not functioning properly. And the spread of cancer (“metastasis”) seems to be intimately related to the lymphatic system as the cancer cells use the lymphatic vessels as pathways to travel within the body.

Unlocking the drains

Mon, 01 Aug 2005 00:00:00 +0000

Nice article by Phyllida Brown in Nature describing the discovery of the VEGF-C/VEGFR-3 signalling axis, and how research on the lymphatic system turned into a hot topic: https://www.nature.com/articles/436456a .

FEBS 2004

Fri, 10 Sep 2004 00:00:00 +0000

My poster for the FEBS 2004 conference in Warsaw.

What you should know about VEGF-C

Wed, 03 Sep 2003 00:00:00 +0000

The Best of 2002

Fri, 20 Dec 2002 00:00:00 +0000

Michael Jeltsch’s PhD thesis

Mon, 25 Nov 2002 00:00:00 +0000

My doctoral thesis has been published: Michael Jeltsch VEGFR-3 Ligands and Lymphangiogenesis, Helsinki 2002. The public defence will take place in Biomedicum, Helsinki, on November 29th, 2002.

Lab seminar: Cystine knot proteins

Thu, 22 Aug 2002 00:00:00 +0000

Lymphatics in Different Vertebrate Classes

Fri, 25 Jan 2002 00:00:00 +0000

Dissecting Lymphangiogenesis and Angiogenesis

Fri, 07 Sep 2001 00:00:00 +0000

The presentation slides below are for some reason extremely slow to load (about 2 minutes). You need to be very patient! Flash support has been ended by all current browsers, and this page uses Ruffle , a Flash Player emulator written in Rust, to resurrect these dead files.

Lab seminar: Chicken kick ass

Wed, 13 Jun 2001 00:00:00 +0000

Kloster Seeon Conference (October 1-4, 2000): Exploring the VEGF protein space

Wed, 01 Nov 2000 00:00:00 +0000

I participated in the first International Kloster Seeon “Angiogenesis” Meeting" https://www.vwfb.de/seeon-meetings in Germany, with a poster about VEGF growth factors. The venue was excellent: a former Benedictine monastery in Upper Bavaria .

Projects in the Molecular/Cancer Biology Laboratory

Fri, 31 Dec 1999 00:00:00 +0000

Available Downloads

Get the poster in PDF format.

Download PDF

The Alphabet of Angiogenesis

Tue, 01 Jun 1999 00:00:00 +0000

Available Downloads

Get the poster in PDF format.

Download PDF

The Alphabet of Angiogenesis

Thu, 31 Dec 1998 00:00:00 +0000

Available Downloads

Get the poster in PDF format.

Download PDF

Recombinant Protein Production, CAM Assays, VEGF-D, Transgenic Mice

Sat, 01 Nov 1997 00:00:00 +0000

Vascular Biology on Michael’s Domain

Just another type of fish

ADAMTS18 regulates ECM turnover via fibronectin cleavage

Delivery still limits VEGF therapy

An impossible overlap-extension PCR

VEGFC-loaded Lignin Nanoparticles

Billion-dollar gamble

Our lab won't go bancrupt in 2025!

What do we really know about lipedema?

Do fish have difficulty breathing?

Do fish have lymphatics?

Congratulations, Dr. Khushbu Rauniyar!

Cutting-edge vascular biology continues at the Wihuri Research Institute

OMG: T. rex did not have VEGF-B!

Bioactive VEGF-C from E. coli without in-vitro folding!

Making the cut: Why VEGF-C != VEGF-C

The evolution of PDGF/VEGF growth factors

"Bioactive VEGF-C from E. coli cytoplasm" preprint online

Lymphatics as the origin of the fish secondary vascular system

KLK3: tumorigenic or not?

3. Swiss Lymphsymposium

Searching for a lymphedema drug

MDPI peer review reviewed

Preprint and Open Review

Review published in Duodecim: Lymphatics and the eye

VEGF-C protects blood cell production

Dr. Sawan K. Jha: Mechanism of VEGF-C Activation […]

Lymphatics and the eye

Lymphologie 2019

ISK 2019

Re-purposing the growth factor VEGF-C

Lymphologische (Grundlagen-)Forschung: wie funktioniert das?

Vortrag für den 43. Jahreskongress der Deutschen Desellschaft für Lymphologie

KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D

1000+ citations

International Vascular Biology Meeting 2018 organizational feedback

Minireview about key molecules in lymphatic development, function, and identification

IVBM 2018 & 2020 (poster, talk, and virtual poster walk through)

VEGF-C Re­view in Fron­ti­ers in Bioen­gin­eer­ing and Bi­o­tech­no­logy

20th International Vascular Biology Meeting in Helsinki, Finland

Lymphologica 2017

Essentials facts about VEGF-C in lymphology

A Very Short History of Antiangiogenic Tumor Treatment

Angiogenesis landmark publications

Science good, coffee bad

RPU Seminar 2016

Available Downloads

Centrifugal and centripetal embryonic lymphatic development

This year's Nobel prizes

Erkrankungen des Lymphgefäßsystems (Diseases of the Lymphatic System)

Lymphangiogenesis in health and disease

Available Downloads

Best paper award

38. Annual Congress of the German Society for Lymphology

New Mechanisms of Lymphangiogenesis and Lymphedema

From the molecular biological foundations to causal treatment options for diseases of the lymphatic system

We got featured by Circulation!

The molecular basis of Hennekam syndrome

SVS or lymphatic system?

Historic articles about the lymphatic system

Permission to self-archive

A Nobel Prize for angiogenesis research?

Self Archiving and Open Access

Lymphangiogenese-Regulation durch Wachstumsfaktoren

Introduction into lymphatic research

Structure/function relationships within the VEGF/VEGF receptor families

VEGF-C/VEGFR-2 complex structure took 13 years to solve

Recombinant proteins

Judah Folkman dies at age 74

Growth factor regulation of lymphangiogenesis

Unlocking the drains

FEBS 2004

What you should know about VEGF-C

The Best of 2002

Michael Jeltsch’s PhD thesis

Lab seminar: Cystine knot proteins

Lymphatics in Different Vertebrate Classes

Dissecting Lymphangiogenesis and Angiogenesis

Lab seminar: Chicken kick ass

Kloster Seeon Conference (October 1-4, 2000): Exploring the VEGF protein space

VEGF-C Review in Frontiers in Bioengineering and Biotechnology