Neuropilin-1 (NRP 1) and NRP2 are related transmembrane receptors that function as mediators of neuronal guidance and angiogenesis. NRPs bind members of the class 3 semaphorin family, regulators of neuronal guidance, and of the vascular endothelial growth factor (VEGF) family of angiogenesis factors. There is substantial evidence that NRPs serve as mediators of developmental and tumor angiogenesis. NRPs are expressed in endothelial cells (EC) and bind VEGF₁₆₅. NRP1 is a co-receptor for VEGF receptor-2 (VEGFR2) that enhances the binding of VEGF₁₆₅ to VEGFR2 and VEGF₁₆₅-mediated chemotaxis. NRP1 expression is regulated in EC by tumor necrosis factor-α, the transcription factors dHAND and Ets- 1, and vascular injury. During avian blood vessel development NRP I is expressed only in arteries whereas NRP2 is expressed in veins. Transgenic mouse models demonstrate that NRP1 plays a critical role in embryonic vascular development. Overexpression of NRP 1 results in the formation of excess capillaries and hemorrhaging. NRP1 knockouts have defects in yolk sac, embryo and neuronal vascularization, and in development of large vessels in the heart. Tumor cells express NRPs and bind VEGF₁₆₅. NRP1 upregulation is positively correlated with the progression of various tumors. Overexpression of NRP 1 in rat tumor cells results in enlarged tumors and substantially enhanced tumor angiogenesis. On the other hand, soluble NRP1 (sNRP 1) is an antagonist of tumor angiogenesis. Semaphorin 3A binds to EC and tumor cells. It also inhibits EC motility and capillary sprouting in vitro. VEGF₁₆₅