Rap1 promotes VEGFR2 activation and angiogenesis by a mechanism involving integrin αvβ3
Rap1 promotes VEGFR2 activation and angiogenesis by a mechanism involving integrin αvβ3
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DOI：
10.1182/blood-2011-04-349282
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发表时间：
2011-08-18
期刊：
影响因子：
20.3
通讯作者：
Chrzanowska-Wodnicka, Magdalena
中科院分区：
文献类型：
--
作者：
Lakshmikanthan, Sribalaji;Sobczak, Magdalena;Chrzanowska-Wodnicka, Magdalena
血管内皮生长因子（VEGF）通过内皮细胞（ECs）上的血管内皮生长因子受体2（VEGFR2）发挥作用，是血管生成的关键调节因子，血管生成是伤口愈合和肿瘤转移所必需的过程。Rap1a和Rap1b是两种高度同源的小G蛋白，在体内血管生成以及内皮细胞对VEGF的正常反应中都是必需的。在此我们试图确定Rap1促进VEGF介导的血管生成的机制。利用谱系限制性Rap1基因敲除小鼠，我们表明内皮细胞中Rap1的缺失以剂量依赖的方式导致体内血管生成缺陷。利用从Rap1缺陷小鼠获得的内皮细胞，我们证明Rap1b促进VEGF - VEGFR2激酶活化并调节整合素活化。重要的是，依赖于Rap1b的VEGF - VEGFR2活化部分是通过整合素α(v)β(3)介导的。此外，在斑马鱼血管生成的体内模型中，我们证明Rap1b对体节间血管的出芽是必不可少的，已知该过程依赖于VEGF信号传导。利用两种不同的VEGFR2药理抑制剂，我们表明Rap1b和VEGFR2相加作用以控制体内血管生成。我们得出结论，Rap1b通过整合素α(v)β(3)促进内皮细胞中VEGFR2的活化，从而促进VEGF介导的血管生成。这些结果为Rap1在内皮细胞中VEGF信号传导中的作用提供了新的见解。（《血液》2011年；118(7):2015 - 2026）
Vascular endothelial growth factor (VEGF) acting through VEGF receptor 2 (VEGFR2) on endothelial cells (ECs) is a key regulator of angiogenesis, a process essential for wound healing and tumor metastasis. Rap1a and Rap1b, 2 highly homologous small G proteins, are both required for angiogenesis in vivo and for normal EC responses to VEGF. Here we sought to determine the mechanism through which Rap1 promotes VEGF-mediated angiogenesis. Using lineage-restricted Rap1-knockout mice we show that Rap1-deficiency in endothelium leads to defective angiogenesis in vivo, in a dose-dependent manner. Using ECs obtained from Rap1-deficient mice we demonstrate that Rap1b promotes VEGF-VEGFR2 kinase activation and regulates integrin activation. Importantly, the Rap1b-dependent VEGF-VEGFR2 activation is in part mediated via integrin alpha(v)beta(3). Furthermore, in an in vivo model of zebrafish angiogenesis, we demonstrate that Rap1b is essential for the sprouting of intersomitic vessels, a process known to be dependent on VEGF signaling. Using 2 distinct pharmacologic VEGFR2 inhibitors we show that Rap1b and VEGFR2 act additively to control angiogenesis in vivo. We conclude that Rap1b promotes VEGF-mediated angiogenesis by promoting VEGFR2 activation in ECs via integrin alpha(v)beta(3). These results provide a novel insight into the role of Rap1 in VEGF signaling in ECs. (Blood. 2011;118(7):2015-2026)