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

鉴定导致血管生成的内皮细胞特异性信号转导途径

基本信息

批准号：
15591698
负责人：
KANDA Shigeru
金额：
$ 2.24万
依托单位：
Nagasaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591698/
关键词：
endothelial cells differentiation signal transduction Fes Fyn Rho FGF-2 PEDF c-Fes PI3-キナーゼ c-Akt c-Fyn フィブロネクチン

项目摘要

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.

为了识别参与内皮细胞特异性信号转导途径的分子靶标，我们检查了内皮细胞的分化机制和通过酪氨酸激酶Fes.1.FGF-2诱导的毛细血管形态发生需要内源性VEGF-A驱动的信号传导的信号传导途径。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，很大程度上通过粘着斑的分解来调节。2.FGF-2诱导的管形成是通过内源产生的纤连蛋白和a5b1整合素之间的相互作用来调节的。纤连蛋白的产生受T细胞因子-b-连环蛋白复合物的转录调节。3.Fes激活的PI3激酶参与基质源性因子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，从而阻断 FGF-2 诱导的毛细血管形态发生，这表明抑制 Fes 可能不仅仅导致血管生成抑制。虽然 Fyn 并不完全在内皮细胞中表达，但检查 Fyn 下游信号通路将有利于发现内皮细胞特异性信号分子。此外，对c-Fes激活机制的研究可能有助于控制Fes依赖性血管生成。