@article {28, title = {Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins}, journal = {Nat Immunol}, volume = {5}, year = {2004}, month = {2004/Jan/}, pages = {74 - 80}, abstract = {Lymphatic vessels are essential for immune surveillance, tissue fluid homeostasis and fat absorption. Defects in lymphatic vessel formation or function cause lymphedema. Here we show that the vascular endothelial growth factor C (VEGF-C) is required for the initial steps in lymphatic development. In Vegfc-/- mice, endothelial cells commit to the lymphatic lineage but do not sprout to form lymph vessels. Sprouting was rescued by VEGF-C and VEGF-D but not by VEGF, indicating VEGF receptor 3 specificity. The lack of lymphatic vessels resulted in prenatal death due to fluid accumulation in tissues, and Vegfc+/- mice developed cutaneous lymphatic hypoplasia and lymphedema. Our results indicate that VEGF-C is the paracrine factor essential for lymphangiogenesis, and show that both Vegfc alleles are required for normal lymphatic development.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/14634646}, author = {Karkkainen, Marika J and Haiko, Paula and Sainio, Kirsi and Partanen, Juha and Taipale, Jussi and Petrova, Tatiana V and Jeltsch, Michael and Jackson, David G and Talikka, Marja and Rauvala, Heikki and Betsholtz, Christer and Alitalo, Kari} } @article {24, title = {Adenoviral VEGF-C overexpression induces blood vessel enlargement, tortuosity, and leakiness but no sprouting angiogenesis in the skin or mucous membranes}, journal = {FASEB J}, volume = {16}, year = {2002}, month = {2002/Jul/}, pages = {1041 - 9}, abstract = {Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are important regulators of blood and lymphatic vessel growth and vascular permeability. The VEGF-C/VEGFR-3 signaling pathway is crucial for lymphangiogenesis, and heterozygous inactivating missense mutations of the VEGFR-3 gene are associated with hereditary lymphedema. However, VEGF-C can have potent effects on blood vessels because its receptor VEGFR-3 is expressed in certain blood vessels and because the fully processed form of VEGF-C also binds to the VEGFR-2 of blood vessels. To characterize the in vivo effects of VEGF-C on blood and lymphatic vessels, we have overexpressed VEGF-C via adenovirus- and adeno-associated virus-mediated transfection in the skin and respiratory tract of athymic nude mice. This resulted in dose-dependent enlargement and tortuosity of veins, which, along with the collecting lymphatic vessels were found to express VEGFR-2. Expression of angiopoietin 1 blocked the increased leakiness of the blood vessels induced by VEGF-C whereas vessel enlargement and lymphangiogenesis were not affected. However, angiogenic sprouting of new blood vessels was not observed in response to AdVEGF-C or AAV-VEGF-C. These results show that virally produced VEGF-C induces blood vessel changes, including vascular leak, but its angiogenic potency is much reduced compared with VEGF in normal skin.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/12087065}, author = {Saaristo, Anne and Veikkola, Tanja and Enholm, Berndt and Hyt{\"o}nen, Maija and Arola, Johanna and Pajusola, Katri and Turunen, Pa{\"\i}vi and Jeltsch, Michael and Karkkainen, Marika J and Kerjaschki, Dontscho and Bueler, Hansruedi and Yl{\"a}-Herttuala, Seppo and Alitalo, Kari} }