Vascular endothelial growth factor receptor 3 in hypoxia‐induced vascular development

Reduced tissue oxygen tension (hyp‐oxia) is appreciated as an efficient stimulus for neovas‐cularization. The effect of hypoxia on the very first stages of vascular development is, however, less well characterized. Here we show that hypoxic conditions (1% O 2 ) potently stimulated formation of an extensive vascular network during a discrete stage of mouse embryonal stem cell differentiation. The morphologi‐cal changes correlated with an expanding pool of endothelial cells and with activation of the vascular endothelial growth factor‐d (Vegf‐d) and Vegf recep‐tor‐3 genes. VEGF receptor‐3 expression was confined to vascular endothelial cells and analysis of the lym‐phatic marker Prox‐1 revealed no expansion of lym‐phatic endothelial cells. Administration of neutralizing antibodies against either VEGF receptor‐3 or VEGF receptor‐2 impaired vascular network formation, whereas neutralizing antibodies against VEGF recep‐tor‐1 potentiated development of immature vascular structures. In addition, sequestering of VEGF recep‐tor‐3 ligands reduced vascularization in a manner sim‐ilar to neutralization of VEGF receptor‐3. We conclude that hypoxia‐driven vascular development requires the activity of VEGF receptor‐3.−Nilsson, I., Rolny, C., Wu, Y., Pytowski, B., Hicklin, D., Alitalo, K., Claesson‐Welsh, L., Wennstro¨m, S. Vascular endothelial growth factor receptor‐3 in hypoxia‐induced vascular develop‐ment. FASEB J. 18, 1507–1515 (2004)