VEGFR2-PLCγ1 axis is essential for endothelial specification of VEGFR2+ vascular progenitor cells
VEGFR2-PLCγ1 axis is essential for endothelial specification of VEGFR2+ vascular progenitor cells
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DOI：
10.1242/jcs.049908
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发表时间：
2009-09-15
影响因子：
4
通讯作者：
Miyazawa, Keiji
中科院分区：
文献类型：
--
作者：
Sase, Hitoshi;Watabe, Tetsuro;Miyazawa, Keiji
血管内皮生长因子受体2（VEGFR 2）在血管发生中起着至关重要的作用，血管发生是一个涉及细胞增殖、迁移和分化的过程。然而，VEGFR 2信号传导指导VEGFR 2（+）中胚层祖细胞血管内皮分化的分子机制还不清楚。在这项研究中，我们使用小鼠胚胎干细胞衍生的VEGFR 2（+）细胞的体外分化系统，研究了VEGFR 2下游的信号转导通路，用于内皮分化。使用由VEGFR 2和VEGFR 3（VEGFR家族的第三个成员）组成的嵌合受体，我们发现通过VEGFR 2的酪氨酸1175（Y1175，对应于小鼠Y1173）的信号传导对于内皮分化的两个过程是至关重要的：VEGFR 2（+）祖细胞的内皮特化和随后的内皮细胞（EC）的存活。此外，我们发现，磷脂酶C γ 1（PLC γ 1），通过磷酸化Y1175与VEGFR 2相互作用，是内皮细胞特化的诱导剂。与VEGFR 2相反，VEGFR 3不传递VEGFR 2（+）细胞的内皮分化信号。我们发现VEGFR 3不激活PLC γ 1，尽管VEGFR 3具有支持内皮细胞存活的能力。综上所述，这些发现表明VEGFR 2-PLC γ 1信号传递引起VEGFR 2的独特功能，从而使内皮细胞从血管祖细胞分化。
Vascular endothelial growth factor receptor 2 (VEGFR2) plays crucial roles in vasculogenesis, a process involving cell proliferation, migration and differentiation. However, the molecular mechanism by which VEGFR2 signaling directs vascular endothelial differentiation of VEGFR2(+) mesodermal progenitors is not well understood. In this study, we examined the signal transduction pathway downstream of VEGFR2 for endothelial differentiation using an in vitro differentiation system of mouse embryonic stem-cell-derived VEGFR2(+) cells. Using chimeric receptors composed of VEGFR2 and VEGFR3, the third member of the VEGFR family, we found that signaling through tyrosine 1175 (Y1175, corresponding to mouse Y1173) of VEGFR2 is crucial for two processes of endothelial differentiation: endothelial specification of VEGFR2(+) progenitors, and subsequent survival of endothelial cells (ECs). Furthermore, we found that phospholipase C gamma 1 (PLC gamma 1), which interacts with VEGFR2 through phosphorylated Y1175, is an inducer of endothelial specification. In contrast to VEGFR2, VEGFR3 does not transmit a signal for endothelial differentiation of VEGFR2(+) cells. We found that VEGFR3 does not activate PLC gamma 1, although VEGFR3 has the ability to support endothelial cell survival. Taken together, these findings indicate that VEGFR2-PLC gamma 1 signal relay gives rise to the unique function of VEGFR2, thus enabling endothelial differentiation from vascular progenitors.