02457nas a2200433   4500008004100000022001300041245009100054210006900145260001600214300001700230490000700247520118000254100001801434700002101452700001901473700002301492700001801515700001901533700002501552700001501577700001801592700002201610700002301632700002001655700002401675700002301699700002001722700001601742700002001758700002101778700002001799700002201819700002801841700001801869700002001887700002301907700002101930856007201951       2025                        eng d  a1934590900aFetal-like reversion in the regenerating intestine is regulated by mesenchymal asporin0 aFetallike reversion in the regenerating intestine is regulated b  cJan-04-2025  a613 - 626.e80 v323 aMesenchymal cells and the extracellular matrix (ECM) support epithelium during homeostasis and regeneration. However, the role of the mesenchyme in epithelial conversion into a fetal-like regenerative state after damage is not known. We modeled epithelial regeneration by culturing intestinal epithelium on decellularized small intestinal scaffolds (iECM) and identify asporin (Aspn), an ECM-bound proteoglycan, as a critical mediator of epithelial fetal-like reprogramming. After damage, transient increase in Aspn expression by the pericryptal fibroblasts induces epithelial transforming growth factor b (TGF-b)-signaling via CD44 and promotes timely epithelial reprogramming. Temporal control of Aspn is lost in old mice, and after damage, the persistently high level of Aspn stagnates epithelium in the regenerative state. Increase in Wnt signaling can resolve the stagnated regenerative program of the old epithelium, promoting restoration of tissue function. In summary, we establish a platform for modeling epithelial injury responses ex vivo and show that the mesenchymal Aspn-producing niche modulates tissue repair by regulating epithelial fetal-like reprogramming.1 aIqbal, Sharif1 aAndersson, Simon1 aNesta, Ernesta1 aPentinmikko, Nalle1 aKumar, Ashish1 aJha, Sawan, K.1 aBorshagovski, Daniel1 aWebb, Anna1 aGebert, Nadja1 aViitala, Emma, W.1 aRitchie, Alexandra1 aScharaw, Sandra1 aKuuluvainen, Emilia1 aLarsen, Hjalte, L.1 aSaarinen, Tuure1 aJuuti, Anne1 aRistimäki, Ari1 aJeltsch, Michael1 aOri, Alessandro1 aVarjosalo, Markku1 aPietiläinen, Kirsi, H.1 aOllila, Saara1 aJensen, Kim, B.1 aOudhoff, Menno, J.1 aKatajisto, Pekka  uhttps://www.sciencedirect.com/science/article/pii/S193459092500048700566nas a2200157   4500008004100000022001400041245010100055210006900156260001600225100002100241700002300262700001900285700002500304700002100329856005800350       2024                        eng d  a1464-793100aThe relationship between the secondary vascular system and the lymphatic vascular system in fish0 arelationship between the secondary vascular system and the lymph  cApr-06-20261 aPanara, Virginia1 aVaraliová, Zuzana1 aWilting, Jörg1 aKoltowska, Katarzyna1 aJeltsch, Michael  uhttps://onlinelibrary.wiley.com/doi/10.1111/brv.1311402952nas a2200289   4500008004100000245008800041210006900129260001200198300001200210490000800222520202000230653002802250653002202278653002402300653001702324653004802341100002102389700001302410700002102423700002302444700002102467700002302488700003002511700001802541700002102559856008202580       2016                        eng d00aFunctional Importance of a Proteoglycan Co-Receptor in Pathologic Lymphangiogenesis0 aFunctional Importance of a Proteoglycan CoReceptor in Pathologic  c05/2016  a210-2210 v1193 aRationale: Lymphatic vessel growth is mediated by major pro-lymphangiogenic factors such as VEGF-C and -D, among other endothelial effectors. Heparan sulfate is a linear polysaccharide expressed on proteoglycan core proteins on cell-membranes and matrix, playing roles in angiogenesis, although little is known regarding any function(s) in lymphatic remodeling in vivo.
Objective: To explore the genetic basis and mechanisms whereby heparan sulfate proteoglycans mediate pathologic lymphatic remodeling.
Methods and Results: Lymphatic endothelial deficiency in the major heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1; involved in glycan-chain sulfation) was associated with reduced lymphangiogenesis in pathologic models, including spontaneous neoplasia. Mouse mutants demonstrated tumor-associated lymphatic vessels with apoptotic nuclei. Mutant lymphatic endothelia demonstrated impaired mitogen (Erk) and survival (Akt) pathway signaling as well as reduced VEGF-C mediated protection from starvation-induced apoptosis. Lymphatic endothelial specific Ndst1 deficiency (in Ndst1f/fProx1+/CreERT2 mice) was sufficient to inhibit VEGF-C dependent lymphangiogenesis. Lymphatic heparan sulfate deficiency reduced phosphorylation of the major lymphatic growth receptor VEGFR-3 in response to multiple VEGF-C species. Syndecan-4 was the dominantly expressed heparan sulfate proteoglycan in mouse lymphatic endothelia, and pathologic lymphangiogenesis was impaired in Sdc4(-/-) mice. On the lymphatic cell surface, VEGF-C induced robust association between syndecan-4 and VEGFR-3 which was sensitive to glycan disruption. Moreover, VEGFR-3 mitogen and survival signaling was reduced in the setting of Ndst1 or Sdc4 deficiency.
Conclusions: These findings demonstrate the genetic importance of heparan sulfate and the major lymphatic proteoglycan syndecan-4 in pathologic lymphatic remodeling. This may introduce novel future strategies to alter pathologic lymphatic-vascular remodeling.10aendothelial cell growth10aglycosaminoglycan10alymphatic capillary10aProteoglycan10avascular endothelial growth factor receptor1 aJohns, Scott, C.1 aYin, Xin1 aJeltsch, Michael1 aBishop, Joseph, R.1 aSchuksz, Manuela1 aGhazal, Roland, El1 aWilcox-Adelman, Sarah, A.1 aAlitalo, Kari1 aFuster, Mark, M.  uhttp://circres.ahajournals.org/content/early/2016/05/25/CIRCRESAHA.116.30850402227nas a2200193   4500008004100000020002200041245004600063210004100109250000600150260002900156300001200185520168900197100002001886700001901906700002101925700002201946700002701968856003801995       2015                        eng d  a978-3-934371-53-800aThe genetic causes of primary lymphedema.0 agenetic causes of primary lymphedema  a6  aColognebViavital Verlag  a210-2293 aEnglish:
Primary lymphedema can be treated, but not cured. In addition, their diagnosis is due to heterogeneous phenotypes often ambiguous. However, these problems can be tackled by identifying the edema-causing genetic lesions to yield unambiguous diagnoses and by developing specific treatments that address the underlying, molecular cause. New developments in molecular biology are providing the necessary tools for these tasks and in the recent years the genetic causes of many forms of primary lymphedema have been identified, notably by exome sequencing. For a significant proportion of lymphatic disorders multifactorial genetic causes are suspected.
This chapter provides an overview of the current knowledge on the genetic origin, the categorization as well as the molecular and biochemical causes of primary lymphedema.

German:
Primäre Lymphödeme sind behandelbar, aber nicht heilbar. Zudem ist die Diagnostik aufgrund heterogener Phänotypen oft nicht eindeutig. Um diese Probleme anzugehen, müssen die das Ödem verursachenden genetischen Ursachen gefunden, diagnostiziert und gezielt behandelt werden. Die hierzu notwendigen Techniken liefern die neuen Entwicklungen in der Molekularbiologie. Insbesondere durch die Technik der Exom-Sequenzierung wurden in den letzten Jahren die genetischen Ursachen vieler primärer Lymphödeme identifiziert. Für einen weiteren großen Anteil dieser Erkrankungen werden multifaktorielle genetische Dispositionen vermutet.
Dieses Kapitel gibt einen Überblick über den derzeitigen Kenntnisstand der genetischen Ursachen, der Kategorisierung sowie der molekularbiologischen und biochemischen Grundlagen primärer Lymphödeme.1 aMattonet, Kenny1 aWilting, Jörg1 aJeltsch, Michael1 aWeissleder, Horst1 aSchuchhardt, Christian  uhttps://jeltsch.org/Mattonet2015a00835nas a2200301   4500008004100000022002200041245002800063210002400091260003800115300001200153653000800165653001700173653001000190653002100200653002100221653002300242653000900265653000900274653002500283100002100308700002100329700002100350700002600371700001800397700002300415700001800438856007700456       2015                        eng d  a978-3-319-11888-800aThe TIE Receptor Family0 aTIE Receptor Family  bSpringer International Publishing  a743-77510aANG10aAngiopoietin10aANGPT10aEndothelial cell10aLymphatic vessel10aNeovascularization10aTIE110aTIE210aVascular dysfunction1 aSaharinen, Pipsa1 aJeltsch, Michael1 aSantoyo, MayteM.1 aLeppänen, Veli-Matti1 aAlitalo, Kari1 aWheeler, Deric, L.1 aYarden, Yosef  uhttps://link.springer.com/content/pdf/10.1007%2F978-3-319-11888-8_16.pdf02098nas a2200385   4500008004100000245011800041210006900159260001400228300001400242490000700256520095200263100001301215700001501228700001901243700001901262700001601281700002001297700002101317700002001338700002401358700002901382700002001411700002901431700001601460700002501476700002501501700002301526700002101549700001901570700001801589700001801607700002101625700001701646856004901663       2008                        eng d00aReevaluation of the role of VEGF-B suggests a restricted role in the revascularization of the ischemic myocardium0 aReevaluation of the role of VEGFB suggests a restricted role in   c2008/Sep/  a1614 - 200 v283 aOBJECTIVE: The endogenous role of the VEGF family member vascular endothelial growth factor-B (VEGF-B) in pathological angiogenesis remains unclear. METHODS AND RESULTS: We studied the role of VEGF-B in various models of pathological angiogenesis using mice lacking VEGF-B (VEGF-B(-/-)) or overexpressing VEGF-B(167). After occlusion of the left coronary artery, VEGF-B deficiency impaired vessel growth in the ischemic myocardium whereas, in wild-type mice, VEGF-B(167) overexpression enhanced revascularization of the infarct and ischemic border zone. By contrast, VEGF-B deficiency did not affect vessel growth in the wounded skin, hypoxic lung, ischemic retina, or ischemic limb. Moreover, VEGF-B(167) overexpression failed to enhance vascular growth in the skin or ischemic limb. CONCLUSIONS: VEGF-B appears to have a relatively restricted angiogenic activity in the ischemic heart. These insights might offer novel therapeutic opportunities.1 aLi, Xuri1 aTjwa, Marc1 aVan Hove, Inge1 aEnholm, Berndt1 aNeven, Elke1 aPaavonen, Karri1 aJeltsch, Michael1 aJuan, Toni Diez1 aSievers, Richard, E1 aChorianopoulos, Emmanuel1 aWada, Hiromichi1 aVanwildemeersch, Maarten1 aNoel, Agnes1 aFoidart, Jean-Michel1 aSpringer, Matthew, L1 aDegenfeld, Georges1 aDewerchin, Mieke1 aBlau, Helen, M1 aAlitalo, Kari1 aEriksson, Ulf1 aCarmeliet, Peter1 aMoons, Lieve  uhttp://view.ncbi.nlm.nih.gov/pubmed/1851169902705nas a2200229   4500008004100000245014300041210006900184260001400253300001400267490000700281520193200288100002502220700002202245700002102267700002102288700002102309700002602330700002202356700003002378700001802408856004902426       2008                        eng d00aThe tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesis0 atyrosine kinase inhibitor cediranib blocks ligandinduced vascula  c2008/Jun/  a4754 - 620 v683 aSolid tumors express a range of factors required to sustain their growth and promote their dissemination. Among these are vascular endothelial growth factor-A (VEGF-A), the key angiogenic stimulant, and VEGF-C, a primary mediator of lymphangiogenesis. Small molecule tyrosine kinase inhibitors offer the potential to inhibit more than one kinase and impede tumor growth by multiple mechanisms. However, their potency toward individual targets can vary. Cediranib (RECENTIN; AZD2171) is an inhibitor of VEGF signaling that has been shown in experimental models to prevent VEGF-A-induced angiogenesis and primary tumor growth, yet the effects of cediranib on VEGF receptor (VEGFR)-3-mediated endothelial cell function and lymphangiogenesis are unknown. To better understand the activity of cediranib against VEGFR-3 and its associated signaling events compared with its activity against VEGFR-2, we used the receptor-specific ligands VEGF-E and VEGF-C156S. In human endothelial cells, cediranib inhibited VEGF-E-induced phosphorylation of VEGFR-2 and VEGF-C156S-induced phosphorylation of VEGFR-3 at concentrations of </=1nmol/L and inhibited activation of downstream signaling molecules. Additionally, cediranib blocked VEGF-C156S-induced and VEGF-E-induced proliferation, survival, and migration of lymphatic and blood vascular endothelial cells. In vivo, cediranib (6 mg/kg/d) prevented angiogenesis and lymphangiogenesis induced by VEGF-E-expressing and VEGF-C156S-expressing adenoviruses, respectively. Cediranib (6 mg/kg/day) also blocked angiogenesis and lymphangiogenesis induced by adenoviruses expressing VEGF-A or VEGF-C and compromised the blood and lymphatic vasculatures of VEGF-C-expressing tumors. Cediranib may, therefore, be an effective means of preventing tumor progression, not only by inhibiting VEGFR-2 activity and angiogenesis, but also by concomitantly inhibiting VEGFR-3 activity and lymphangiogenesis.1 aHeckman, Caroline, A1 aHolopainen, Tanja1 aWirzenius, Maria1 aKeskitalo, Salla1 aJeltsch, Michael1 aYlä-Herttuala, Seppo1 aWedge, Stephen, R1 aJürgensmeier, Juliane, M1 aAlitalo, Kari  uhttp://view.ncbi.nlm.nih.gov/pubmed/1855952202828nas a2200181   4500008004100000245013000041210006900171260007100240520211900311100002602430700002202456700002102478700002102499700002102520700002302541700003002564856005202594       2007                        eng d00aInhibiton of VEGF-C-induced VEGFR-3 activity and lymphatic endothelial cell function by the tyrosine kinase inhibitor AZD21710 aInhibiton of VEGFCinduced VEGFR3 activity and lymphatic endothel  aLos Angeles, CAbAmerican Association for Cancer Researchc2007///3 aSolid tumors express a range of growth factors required to sustain their growth and promote their dissemination. Among these factors is vascular endothelial growth factor-A (VEGF-A), the key angiogenic stimulant, and VEGF-C, a primary mediator of lymphangiogenesis. Small molecule tyrosine kinase inhibitors can prevent VEGF signaling activity by targeting the VEGF receptors and are an effective approach to impede tumor progression. The indole-ether quinazoline AZD2171 is a highly potent ATP-competitive inhibitor of VEGFR-2 (KDR) kinase, with additional activity against VEGFR-1 (Flt-1) and -3 (Flt-4), that has been shown in experimental models to prevent VEGF-A-induced angiogenesis and primary tumor growth (Wedge et al. Cancer Res 2005;65:4389-4400). For these studies we wished to further assess the ability of AZD2171 to inhibit VEGFR-3 and its associated functions. Upon binding its ligands VEGF-C or -D, VEGFR-3 becomes activated with the resulting signaling cascade eventually translated into increased proliferation, survival and migration of lymphatic and blood vascular endothelial cells. At concentrations of ≤1 nM AZD2171 inhibited VEGFR-3 phosphorylation in porcine aortic endothelial cells selectively expressing the human receptor, and in human dermal microvascular endothelial cells (HDMVECs). In HDMVECs, AZD2171 prevented phosphorylation of signaling molecules downstream of VEGFR-2 and -3, ERK1/2, Akt and CREB, induced by the VEGFR-2 and -3-specific ligands VEGF-E and -C156S, respectively. Additionally, AZD2171 blocked VEGF-E- and -C156S-induced proliferation of both lymphatic and blood vascular endothelial cells at similar concentrations, and prevented ligand-induced endothelial cell cord formation in a Matrigel assay. The effects of AZD2171 on VEGF-C-induced lymphangiogenesis are currently being assessed in vivo. These studies, together with previous results, not only demonstrate that AZD2171 may be an effective means of preventing tumor progression by inhibition of VEGFR-2 activity and angiogenesis, but may also prevent further tumor spread by inhibiting VEGFR-3 activity1 aHeckman, Caroline, A.1 aHolopainen, Tanja1 aWirzenius, Maria1 aKeskitalo, Salla1 aJeltsch, Michael1 aWedge, Stephen, R.1 aJurgensmeier, Juliane, M.  uhttp://dx.doi.org/10.1158/0008-5472.CAN-07-580900372nas a2200133   4500008004100000245001900041210001900060250000700079260001000086100002100096700001800117710001600135856008700151       2006                        eng d00aVEGF Receptors0 aVEGF Receptors  a5.  bSigma1 aJeltsch, Michael1 aAlitalo, Kari1 aWatling, K.  uhttp://www.sigmaaldrich.com/technical-documents/articles/biology/rbi-handbook.html01736nas a2200169   4500008004100000245005000041210005000091260001400141300001200155490000800167520126400175100002101439700002001460700001801480700001901498856004901517       2003                        eng d00aGenesis and pathogenesis of lymphatic vessels0 aGenesis and pathogenesis of lymphatic vessels  c2003/Oct/  a69 - 840 v3143 aThe lymphatic system is generally regarded as supplementary to the blood vascular system, in that it transports interstitial fluid, macromolecules, and immune cells back into the blood. However, in insects, the open hemolymphatic (or lymphohematic) system ensures the circulation of immune cells and interstitial fluid through the body. The Drosophila homolog of the mammalian vascular endothelial growth factor receptor (VEGFR) gene family is expressed in hemocytes, suggesting a close relationship to the endothelium that develops later in phylogeny. Lymph hearts are typical organs for the propulsion of lymph in lower vertebrates and are still transiently present in birds. The lymphatic endothelial marker VEGFR-3 is transiently expressed in embryonic blood vessels and is crucial for their development. We therefore regard the question of whether the blood vascular system or the lymphatic system is primary or secondary as open. Future molecular comparisons should be performed without any bias based on the current prevalence of the blood vascular system over the lymphatic system. Here, we give an overview of the structure, function, and development of the lymphatics, with special emphasis on the recently discovered lymphangiogenic growth factors.1 aJeltsch, Michael1 aTammela, Tuomas1 aAlitalo, Kari1 aWilting, Jörg  uhttp://view.ncbi.nlm.nih.gov/pubmed/1294236201686nas a2200217   4500008004100000245013700041210006900178260001400247300001300261490000700274520102000281100001501301700001501316700001201331700001601343700001401359700001501373700001501388700001701403856004801420       1998                        eng d00aVascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4)0 aVascular endothelial growth factor D VEGFD is a ligand for the t  c1998/Jan/  a548 - 530 v953 aWe have identified a member of the VEGF family by computer-based homology searching and have designated it VEGF-D. VEGF-D is most closely related to VEGF-C by virtue of the presence of N- and C-terminal extensions that are not found in other VEGF family members. In adult human tissues, VEGF-D mRNA is most abundant in heart, lung, skeletal muscle, colon, and small intestine. Analyses of VEGF-D receptor specificity revealed that VEGF-D is a ligand for both VEGF receptors (VEGFRs) VEGFR-2 (Flk1) and VEGFR-3 (Flt4) and can activate these receptors. However. VEGF-D does not bind to VEGFR-1. Expression of a truncated derivative of VEGF-D demonstrated that the receptor-binding capacities reside in the portion of the molecule that is most closely related in primary structure to other VEGF family members and that corresponds to the mature form of VEGF-C. In addition, VEGF-D is a mitogen for endothelial cells. The structural and functional similarities between VEGF-D and VEGF-C define a subfamily of the VEGFs.1 aAchen, M G1 aJeltsch, M1 aKukk, E1 aMäkinen, T1 aVitali, A1 aWilks, A F1 aAlitalo, K1 aStacker, S A  uhttp://view.ncbi.nlm.nih.gov/pubmed/943522902815nas a2200217   4500008004100000245013100041210006900172260001400241300001300255490000800268520214700276100001202423700001702435700002002452700001802472700001502490700001402505700001502519700001502534856004802549       1997                        eng d00aVEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane0 aVEGF and VEGFC specific induction of angiogenesis and lymphangio  c1997/Aug/  a96 - 1090 v1883 aThe lymphangiogenic potency of endothelial growth factors has not been studied to date. This is partially due to the lack of in vivo lymphangiogenesis assays. We have studied the lymphatics of differentiated avian chorioallantoic membrane (CAM) using microinjection of Mercox resin, semi- and ultrathin sectioning, immunohistochemical detection of fibronectin and alpha-smooth muscle actin, and in situ hybridization with VEGFR-2 and VEGFR-3 probes. CAM is drained by lymphatic vessels which are arranged in a regular pattern. Arterioles and arteries are accompanied by a pair of interconnected lymphatics and form a plexus around bigger arteries. Veins are also associated with lymphatics, particularly larger veins, which are surrounded by a lymphatic plexus. The lymphatics are characterized by an extremely thin endothelial lining, pores, and the absence of a basal lamina. Patches of the extracellular matrix can be stained with an antibody against fibronectin. Lymphatic endothelial cells of differentiated CAM show ultrastructural features of this cell type. CAM lymphatics do not possess mediae. In contrast, the lymphatic trunks of the umbilical stalk are invested by a single but discontinuous layer of smooth muscle cells. CAM lymphatics express VEGFR-2 and VEGFR-3. Both the regular pattern and the typical structure of these lymphatics suggest that CAM is a suitable site to study the in vivo effects of potential lymphangiogenic factors. We have studied the effects of VEGF homo- and heterodimers, VEGF/PlGF heterodimers, and PlGF and VEGF-C homodimers on Day 13 CAM. All the growth factors containing at least one VEGF chain are angiogenic but do not induce lymphangiogenesis. PlGF-1 and PlGF-2 are neither angiogenic nor lymphangiogenic. VEGF-C is the first lymphangiogenic factor and seems to be highly chemoattractive for lymphatic endothelial cells. It induces proliferation of lymphatic endothelial cells and development of new lymphatic sinuses which are directed immediately beneath the chorionic epithelium. Our studies show that VEGF and VEGF-C are specific angiogenic and lymphangiogenic growth factors, respectively.1 aOh, S J1 aJeltsch, M M1 aBirkenhäger, R1 aMcCarthy, J E1 aWeich, H A1 aChrist, B1 aAlitalo, K1 aWilting, J  uhttp://view.ncbi.nlm.nih.gov/pubmed/9245515