@article {701,
	title = {Investigation on the role of biallelic variants in VEGF-C found in a patient affected by Milroy-like lymphedema},
	journal = {Molecular Genetics \& Genomic Medicine},
	volume = {00},
	year = {2020},
	month = {Feb-06-2022},
	pages = {e1389},
	issn = {2324-9269},
	doi = {10.1002/mgg3.1389},
	url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/mgg3.1389},
	author = {Mukenge, Sylvain and Jha, Sawan K. and Catena, Marco and Manara, Elena and Lepp{\"a}nen, Veli-Matti and Lenti, Elisa and Negrini, Daniela and Bertelli, Matteo and Brendolan, Andrea and Jeltsch, Michael and Aldrighetti, Luca}
}
@article {708,
	title = {VEGF-C Protects the Integrity of Bone Marrow Perivascular Niche},
	journal = {Blood},
	year = {2020},
	month = {2020/07/31/},
	pages = {accepted - for publication},
	abstract = {Key Points. Vegfc deletion in endothelial or LepR+ cells compromises the bone marrow perivascular niche and hematopoietic stem cell maintenance.Exogenous admin},
	doi = {10.1182/blood.2020005699},
	url = {https://ashpublications.org/blood/article/doi/10.1182/blood.2020005699/463465/VEGF-C-Protects-the-Integrity-of-Bone-Marrow},
	author = {Fang, Shentong and Chen, Shuo and Nurmi, Harri and Lepp{\"a}nen, Veli-Matti and Jeltsch, Michael and Scadden, David T. and Silberstein, Lev and Mikkola, Hanna and Alitalo, Kari}
}
@article {505,
	title = {Ischemia-Reperfusion Injury Enhances Lymphatic Endothelial VEGFR3 and Rejection in Cardiac Allografts},
	journal = {American Journal of Transplantation},
	volume = {16},
	year = {2015},
	month = {12/2015},
	pages = {1160-1172},
	abstract = {Organ damage and innate immunity during heart transplantation may evoke adaptive immunity with serious consequences. Because lymphatic vessels bridge innate and adaptive immunity, they are critical in immune surveillance; however, their role in ischemia{\textendash}reperfusion injury (IRI) in allotransplantation remains unknown. We investigated whether the lymphangiogenic VEGF-C/VEGFR3 pathway during cardiac allograft IRI regulates organ damage and subsequent interplay between innate and adaptive immunity. We found that cardiac allograft IRI, within hours, increased graft VEGF-C expression and lymphatic vessel activation in the form of increased lymphatic VEGFR3 and adhesion protein expression. Pharmacological VEGF-C/VEGFR3 stimulation resulted in early lymphatic activation and later increase in allograft inflammation. In contrast, pharmacological VEGF-C/VEGFR3 inhibition during cardiac allograft IRI decreased early lymphatic vessel activation with subsequent dampening of acute and chronic rejection. Genetic deletion of VEGFR3 specifically in the lymphatics of the transplanted heart recapitulated the survival effect achieved by pharmacological VEGF-C/VEGFR3 inhibition. Our results suggest that tissue damage rapidly changes lymphatic vessel phenotype, which, in turn, may shape the interplay of innate and adaptive immunity. Importantly, VEGF-C/VEGFR3 inhibition during solid organ transplant IRI could be used as lymphatic-targeted immunomodulatory therapy to prevent acute and chronic rejection.},
	doi = {10.1111/ajt.13564},
	url = {http://onlinelibrary.wiley.com/doi/10.1111/ajt.13564/abstract},
	author = {Dashkevich, A. and Raissadati, A. and Syrj{\"a}l{\"a}, S. O. and Zarkada, G. and Ker{\"a}nen, M. A. I. and Tuuminen, R. and Krebs, R. and Anisimov, A. and Jeltsch, M. and Lepp{\"a}nen, V.-M. and Alitalo, K. and Nyk{\"a}nen, A. I. and Lemstr{\"o}m, K. B.}
}
@article {425,
	title = {A truncation allele in vascular endothelial growth factor c reveals distinct modes of signaling during lymphatic and vascular development.},
	journal = {Development},
	volume = {140},
	year = {2013},
	month = {2013 Apr},
	pages = {1497-506},
	abstract = {<p>Vascular endothelial growth factor C (Vegfc) is a secreted protein that guides lymphatic development in vertebrate embryos. However, its role during developmental angiogenesis is not well characterized. Here, we identify a mutation in zebrafish vegfc that severely affects lymphatic development and leads to angiogenesis defects on sensitized genetic backgrounds. The um18 mutation prematurely truncated Vegfc, blocking its secretion and paracrine activity but not its ability to activate its receptor Flt4. When expressed in endothelial cells, vegfc(um18) could not rescue lymphatic defects in mutant embryos, but induced ectopic blood vessel branching. Furthermore, vegfc-deficient endothelial cells did not efficiently contribute to tip cell positions in developing sprouts. Computational modeling together with assessment of endothelial cell dynamics by time-lapse analysis suggested that an autocrine Vegfc/Flt4 loop plays an important role in migratory persistence and filopodia stability during sprouting. Our results suggest that Vegfc acts in two distinct modes during development: as a paracrine factor secreted from arteries to guide closely associated lymphatic vasculature and as an autocrine factor to drive migratory persistence during angiogenesis.</p>},
	keywords = {Alleles, Animals, Animals, Genetically Modified, Autocrine Communication, Blood Vessels, Cell Movement, Codon, Nonsense, Embryo, Nonmammalian, Female, Lymphatic System, Mice, Mice, Knockout, Neovascularization, Physiologic, Paracrine Communication, Protein Isoforms, Signal Transduction, Vascular Endothelial Growth Factor C, Zebrafish, Zebrafish Proteins},
	issn = {1477-9129},
	doi = {10.1242/dev.084152},
	author = {Villefranc, Jacques A and Nicoli, Stefania and Bentley, Katie and Jeltsch, Michael and Zarkada, Georgia and Moore, John C and Gerhardt, Holger and Alitalo, Kari and Lawson, Nathan D}
}
@article {427,
	title = {Critical role of VEGF-C/VEGFR-3 signaling in innate and adaptive immune responses in experimental obliterative bronchiolitis.},
	journal = {Am J Pathol},
	volume = {181},
	year = {2012},
	month = {2012 Nov},
	pages = {1607-20},
	abstract = {<p>Chronic inflammation, a hallmark of obliterative bronchiolitis, is known to induce lymphangiogenesis. We therefore studied the role of lymphangiogenic vascular endothelial growth factor C (VEGF-C), its receptor VEGFR-3, and lymphangiogenesis during development of experimental obliterative bronchiolitis [ie, obliterative airway disease (OAD)] in rat tracheal allografts. The functional importance of VEGF-C was investigated by adenovirus-mediated overexpression of VEGF-C (AdVEGF-C), and by inhibition of VEGF-C activity with VEGFR-3-Ig (AdVEGFR-3-Ig). Analyses included histology, immunohistochemistry, and real-time RT-PCR 10 and 30 days after transplantation. In the course of OAD development, lymphangiogenesis was induced in the airway wall during the alloimmune response, which was reversed by cyclosporine A in a dose-dependent fashion. VEGF-C overexpression in tracheal allografts induced epithelial activation, neutrophil chemotaxis, and a shift toward a Th17 adaptive immune response, followed by enhanced lymphangiogenesis and the development of OAD. In contrast, inhibition of VEGF-C activity with VEGFR-3-Ig inhibited lymphangiogenesis and angiogenesis and reduced infiltration of CD4(+) T cells and the development of OAD. Lymphangiogenesis was linked to T-cell responses during the development of OAD, and VEGF-C/VEGFR-3 signaling modulated innate and adaptive immune responses in the development of OAD in rat tracheal allografts. Our results thus suggest VEGFR-3-signaling as a novel strategy to regulate T-cell responses in the development of obliterative bronchiolitis after lung transplantation.</p>},
	keywords = {Adaptive Immunity, Animals, Bronchiolitis Obliterans, Chemotaxis, Cyclosporine, Dendritic Cells, Dose-Response Relationship, Drug, Down-Regulation, Epithelial Cells, Epithelium, Graft Rejection, Immunity, Innate, Immunoglobulins, Inflammation, Lymphangiogenesis, Macrophages, Neutrophils, Rats, Signal Transduction, Th17 Cells, Trachea, Transplantation, Homologous, Up-Regulation, Vascular Endothelial Growth Factor C, Vascular Endothelial Growth Factor Receptor-3},
	issn = {1525-2191},
	doi = {10.1016/j.ajpath.2012.07.021},
	author = {Krebs, Rainer and Tikkanen, Jussi M and Ropponen, Jussi O and Jeltsch, Michael and Jokinen, Janne J and Yl{\"a}-Herttuala, Seppo and Nyk{\"a}nen, Antti I and Lemstr{\"o}m, Karl B}
}
@article {44,
	title = {VEGF-C/VEGFR-3 Signaling Regulates Inflammatory Response in Development of Obliterative Airway Disease},
	journal = {Journal of Heart and Lung Transplantation},
	volume = {30},
	year = {2011},
	month = {2011//},
	pages = {S118 - S118},
	author = {Krebs, R and Tikkanen, JM and Ropponen, JO and Jeltsch, M and Jokinen, JJ and Yl{\"a}-Herttuala, S and Koskinen, PK and Nyk{\"a}nen, AI and Lemstr{\"o}m, KB}
}
@article {39,
	title = {Claudin-like protein 24 interacts with the VEGFR-2 and VEGFR-3 pathways and regulates lymphatic vessel development},
	journal = {Genes Dev},
	volume = {24},
	year = {2010},
	month = {2010/May/},
	pages = {875 - 80},
	abstract = {The Claudin-like protein of 24 kDa (CLP24) is a hypoxia-regulated transmembrane protein of unknown function. We show here that clp24 knockdown in Danio rerio and Xenopus laevis results in defective lymphatic development. Targeted disruption of Clp24 in mice led to enlarged lymphatic vessels having an abnormal smooth muscle cell coating. We also show that the Clp24(-/-) phenotype was further aggravated in the Vegfr2(+/LacZ) or Vegfr3(+/LacZ) backgrounds and that CLP24 interacts with vascular endothelial growth factor receptor-2 (VEGFR-2) and VEGFR-3 and attenuates the transcription factor CREB phosphorylation via these receptors. Our results indicate that CLP24 is a novel regulator of VEGFR-2 and VEGFR-3 signaling pathways and of normal lymphatic vessel structure.},
	url = {http://view.ncbi.nlm.nih.gov/pubmed/20439428},
	author = {Saharinen, Pipsa and Helotera, Hanna and Miettinen, Juho and Norrmen, Camilla and D{\textquoteright}Amico, Gabriela and Jeltsch, Michael and Langenberg, Tobias and Vandevelde, Wouter and Ny, Annelii and Dewerchin, Mieke and Carmeliet, Peter and Alitalo, Kari}
}
@article {36,
	title = {Reevaluation of the role of VEGF-B suggests a restricted role in the revascularization of the ischemic myocardium},
	journal = {Arterioscler Thromb Vasc Biol},
	volume = {28},
	year = {2008},
	month = {2008/Sep/},
	pages = {1614 - 20},
	abstract = {OBJECTIVE: 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.},
	url = {http://view.ncbi.nlm.nih.gov/pubmed/18511699},
	author = {Li, Xuri and Tjwa, Marc and Van Hove, Inge and Enholm, Berndt and Neven, Elke and Paavonen, Karri and Jeltsch, Michael and Juan, Toni Diez and Sievers, Richard E and Chorianopoulos, Emmanuel and Wada, Hiromichi and Vanwildemeersch, Maarten and Noel, Agnes and Foidart, Jean-Michel and Springer, Matthew L and von Degenfeld, Georges and Dewerchin, Mieke and Blau, Helen M and Alitalo, Kari and Eriksson, Ulf and Carmeliet, Peter and Moons, Lieve}
}
@article {31,
	title = {Functional interaction of VEGF-C and VEGF-D with neuropilin receptors},
	journal = {FASEB J},
	volume = {20},
	year = {2006},
	month = {2006/Jul/},
	pages = {1462 - 72},
	abstract = {Lymphatic vascular development is regulated by vascular endothelial growth factor receptor-3 (VEGFR-3), which is activated by its ligands VEGF-C and VEGF-D. Neuropilin-2 (NP2), known to be involved in neuronal development, has also been implicated to play a role in lymphangiogenesis. We aimed to elucidate the mechanism by which NP2 is involved in lymphatic endothelial cell signaling. By in vitro binding studies we found that both VEGF-C and VEGF-D interact with NP2, VEGF-C in a heparin-independent and VEGF-D in a heparin-dependent manner. We also mapped the domains of VEGF-C and NP2 required for their binding. The functional importance of the interaction of NP2 with the lymphangiogenic growth factors was demonstrated by cointernalization of NP2 along with VEGFR-3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with VEGF-C or VEGF-D. NP2 also interacted with VEGFR-3 in coprecipitation studies. Our results show that NP2 is directly involved in an active signaling complex with the key regulators of lymphangiogenesis and thus suggest a mechanism by which NP2 functions in the development of the lymphatic vasculature.},
	url = {http://view.ncbi.nlm.nih.gov/pubmed/16816121},
	author = {K{\"a}rp{\"a}nen, Terhi and Heckman, Caroline A and Keskitalo, Salla and Jeltsch, Michael and Ollila, Hanna and Neufeld, Gera and Tamagnone, Luca and Alitalo, Kari}
}
@article {20,
	title = {Intravascular adenovirus-mediated VEGF-C gene transfer reduces neointima formation in balloon-denuded rabbit aorta},
	journal = {Circulation},
	volume = {102},
	year = {2000},
	month = {2000/Oct/},
	pages = {2262 - 8},
	abstract = {BACKGROUND: Gene transfer to the vessel wall may provide new possibilities for the treatment of vascular disorders, such as postangioplasty restenosis. In this study, we analyzed the effects of adenovirus-mediated vascular endothelial growth factor (VEGF)-C gene transfer on neointima formation after endothelial denudation in rabbits. For comparison, a second group was treated with VEGF-A adenovirus and a third group with lacZ adenovirus. Clinical-grade adenoviruses were used for the study. METHODS AND RESULTS: Aortas of cholesterol-fed New Zealand White rabbits were balloon-denuded, and gene transfer was performed 3 days later. Animals were euthanized 2 and 4 weeks after the gene transfer, and intima/media ratio (I/M), histology, and cell proliferation were analyzed. Two weeks after the gene transfer, I/M in the lacZ-transfected control group was 0. 57+/-0.04. VEGF-C gene transfer reduced I/M to 0.38+/-0.02 (P:<0.05 versus lacZ group). I/M in VEGF-A-treated animals was 0.49+/-0.17 (P:=NS). The tendency that both VEGF groups had smaller I/M persisted at the 4-week time point, when the lacZ group had an I/M of 0.73+/-0.16, the VEGF-C group 0.44+/-0.14, and the VEGF-A group 0. 63+/-0.21 (P:=NS). Expression of VEGF receptors 1, 2, and 3 was detected in the vessel wall by immunocytochemistry and in situ hybridization. As an additional control, the effect of adenovirus on cell proliferation was analyzed by performing gene transfer to intact aorta without endothelial denudation. No differences were seen in smooth muscle cell proliferation or I/M between lacZ adenovirus and 0.9\% saline-treated animals. CONCLUSIONS: Adenovirus-mediated VEGF-C gene transfer may be useful for the treatment of postangioplasty restenosis and vessel wall thickening after vascular manipulations.},
	url = {http://view.ncbi.nlm.nih.gov/pubmed/11056103},
	author = {Hiltunen, M O and Laitinen, M and Turunen, M P and Jeltsch, M and Hartikainen, J and Rissanen, T T and Laukkanen, J and Niemi, M and Kossila, M and H{\"a}kkinen, T P and Kivel{\"a}, A and Enholm, B and Mansukoski, H and Turunen, A M and Alitalo, K and Yl{\"a}-Herttuala, S}
}
