Necl-5/Poliovirus Receptor Interacts With VEGFR2 and Regulates VEGF-Induced Angiogenesis
Necl-5/Poliovirus Receptor Interacts With VEGFR2 and Regulates VEGF-Induced Angiogenesis
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DOI：
10.1161/circresaha.111.256834
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发表时间：
2012-03-02
影响因子：
20.1
通讯作者：
Rikitake, Yoshiyuki
中科院分区：
文献类型：
--
作者：
Kinugasa, Mitsuo;Amano, Hisayuki;Rikitake, Yoshiyuki
基本原理：血管内皮生长因子（VEGF）是一种主要的促血管生成剂，通过与VEGF受体2（VEGFR 2）结合发挥其促血管生成作用，VEGF受体2的活性通过与其他细胞表面蛋白（包括整合素α（v）β（3））的直接相互作用来调节。目的：研究Necl-5/脊髓灰质炎病毒受体（Necl-5/poliovirus receptor，Necl-5/poliovirus receptor，Necl-5/poliovirus receptor）对VEGFR 2与整合素α（v）β（3）相互作用的调控作用，阐明Necl-5在VEGF诱导的血管生成中的作用。Necl-5-敲除小鼠显示血管发育无明显缺陷;然而，后肢缺血后血流恢复和植入基质胶塞中VEGF诱导的新血管形成在Necl-5-敲除小鼠中受损。为了阐明Necl-5调控血管生成的机制，我们研究了Necl-5在VEGF诱导的体外血管生成反应中的作用。在人脐静脉内皮细胞（HUVECs）中通过siRNA敲低Necl-5抑制VEGF诱导的Matrigel上的毛细血管样网络形成、迁移和增殖，并且相反地，增强凋亡。免疫共沉淀分析显示Necl-5与VEGFR 2的相互作用，并且Necl-5的敲低阻止了VEGF诱导的整合素α（v）β（3）与VEGFR 2的相互作用。Necl-5的敲低抑制了VEGFR 2介导的下游促血管生成和存活信号的激活，包括Rap 1、Akt和内皮型一氧化氮合酶。这些结果证明了Necl-5在血管生成中的关键作用，并表明Necl-5可以通过控制VEGFR 2与整合素α（v）β（3）的相互作用来调节VEGF诱导的血管生成，以及VEGFR 2介导的Rap 1-Akt信号通路。(Circ Res. 2012;110：716-726）。
Rationale: Vascular endothelial growth factor (VEGF), a major proangiogenic agent, exerts its proangiogenic action by binding to VEGF receptor 2 (VEGFR2), the activity of which is regulated by direct interactions with other cell surface proteins, including integrin alpha(v)beta(3). However, how the interaction between VEGFR2 and integrin alpha(v)beta(3) is regulated is not clear.Objective: To investigate whether Necl-5/poliovirus receptor, an immunoglobulin-like molecule that is known to bind integrin alpha(v)beta(3), regulates the interaction between VEGFR2 and integrin alpha(v)beta(3), and to clarify the role of Necl-5 in the VEGF-induced angiogenesis.Methods and Results: Necl-5-knockout mice displayed no obvious defect in vascular development; however, recovery of blood flow after hindlimb ischemia and the VEGF-induced neovascularization in implanted Matrigel plugs were impaired in Necl-5-knockout mice. To clarify the mechanism of the regulation of angiogenesis by Necl-5, we investigated the roles of Necl-5 in the VEGF-induced angiogenic responses in vitro. Knockdown of Necl-5 by siRNAs in human umbilical vein endothelial cells (HUVECs) inhibited the VEGF-induced capillary-like network formation on Matrigel, migration, and proliferation, and conversely, enhanced apoptosis. Coimmunoprecipitation assays showed the interaction of Necl-5 with VEGFR2, and knockdown of Necl-5 prevented the VEGF-induced interaction of integrin alpha(v)beta(3) with VEGFR2. Knockdown of Necl-5 suppressed the VEGFR2-mediated activation of downstream proangiogenic and survival signals, including Rap1, Akt, and endothelial nitric oxide synthase.Conclusions: These results demonstrate the critical role of Necl-5 in angiogenesis and suggest that Necl-5 may regulate the VEGF-induced angiogenesis by controlling the interaction of VEGFR2 with integrin alpha(v)beta(3), and the VEGFR2-mediated Rap1-Akt signaling pathway. (Circ Res. 2012;110:716-726.)