Identification of endothelial cell-specific signal transduction pathways leading to angiogenesis

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To identity the molecular targets, which are involved in endothelial cell-specific signal transduction pathways, we examined the mechanism of differentiation of endothelial cells and signaling pathways through tyrosine kinase Fes.1.FGF-2-induced capillary morphogenesis required endogenous VEGF-A-driven signaling. In addition, FGF-2-induccd activation of Fyn, which inactivates Rho through activating Rho GAP, is involved in capillary morphogenesis, largely regulated by disassembly of focal adhesions.2.FGF-2-induced tube formation was regulated by the interaction between endogenously produced fibronectin and a5b1 integrin. Fibronectin production was transcriptionally regulated by T cell factor-b-catenin complex.3.PI3-kinase activated through Fes was involved in stromal-derived factor 1a- and sonic hedgehog-induced differentiation of endothelial cells. However, pigment epithelium-derived factor blocked FGF-2induced capillary morphogenesis by down-regulation of Fyn activity through Fes, suggesting that inhibition of Fes may not simply lead to angiogenesis inhibition.While Fyn is not exclusively expressed in endothelial cells, examination of signaling pathways downstream of Fyn would be favorable to find endothelial cell-specific signaling molecules. In addition, studies of the mechanisms underlying the activation of c-Fes may be helpful to control Fes-dependent angiogenesis.