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

为了确定参与内皮细胞特异性信号转导通路的分子靶点，我们研究了内皮细胞分化的机制和酪氨酸激酶Fes介导的信号转导通路。1. FGF-2诱导的毛细血管形态发生需要内源性VEGF-A驱动的信号转导。此外，FGF-2诱导的Fyn激活（通过激活Rho GAP使Rho失活）参与毛细血管形态发生，主要受粘着斑分解的调节。2.FGF-2诱导的管形成受内源性产生的纤连蛋白和a5 b1之间的相互作用的调节。整合素。纤维连接蛋白的产生受T细胞因子-b-连环蛋白复合物的转录调控。3.通过Fes激活的PI 3-激酶参与了基质衍生因子1a和音刺猬诱导的内皮细胞分化。然而，色素上皮衍生因子通过Fes下调Fyn活性而阻断FGF-2诱导的毛细血管形态发生，这表明Fes的抑制可能不仅仅导致血管生成的抑制。此外，研究c-Fes激活的机制可能有助于控制Fes依赖的血管生成。

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.