VEGF-A Stimulates STAT3 Activity via Nitrosylation of Myocardin to Regulate the Expression of Vascular Smooth Muscle Cell Differentiation Markers.
VEGF-A Stimulates STAT3 Activity via Nitrosylation of Myocardin to Regulate the Expression of Vascular Smooth Muscle Cell Differentiation Markers.
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VEGF-A 通过心肌素的亚硝基化刺激 STAT3 活性，调节血管平滑肌细胞分化标志物的表达
DOI：
10.1038/s41598-017-02907-6
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发表时间：
2017-06-01
影响因子：
4.6
通讯作者：
Zhang TC
中科院分区：
文献类型：
--
作者：
Liao XH;Xiang Y;Li H;Zheng L;Xu Y;Xi Yu C;Li JP;Zhang XY;Xing WB;Cao DS;Bao LY;Zhang TC
血管内皮生长因子A（VEGF-A）是血管生成的关键因子。VEGF-A能够影响诸如微管形成和血管平滑肌细胞（VSMC）增殖等细胞过程，但对介导VEGF-A诱导的VSMC表型转换的实际信号传导事件知之甚少。在这份报告中，我们描述了一个复杂的VEGF-A诱导的信号级联反应，涉及VEGFR 2，STAT 3，和Myocardin的鉴定。我们证明VEGF-A通过VEGFR 2/STAT 3介导的上调Cyclin D1和PCNA等标记物的增殖来促进VSMC增殖。具体来说，VEGF-A导致Myocardin的亚硝基化，削弱其促进收缩标志物表达的作用，并且无法抑制STAT 3的激活。这些结果进一步证实了一氧化氮和S-亚硝基化在血管生成中的重要性，并为VEGF-A诱导的VSMC表型转换提供了一个机制途径。此外，Myocardin、GSNOR和GSNO可以形成负反馈回路来调节VSMC表型转换。因此，发现这种相互作用的信号通路网络为血管生成依赖性疾病提供了新的和意想不到的治疗靶点。
Vascular endothelial growth factor A (VEGF-A) is a pivotal player in angiogenesis. It is capable of influencing such cellular processes as tubulogenesis and vascular smooth muscle cell (VSMC) proliferation, yet very little is known about the actual signaling events that mediate VEGF-A induced VSMC phenotypic switch. In this report, we describe the identification of an intricate VEGF-A-induced signaling cascade that involves VEGFR2, STAT3, and Myocardin. We demonstrate that VEGF-A promotes VSMC proliferation via VEGFR2/STAT3-mediated upregulating the proliferation of markers like Cyclin D1 and PCNA. Specifically, VEGF-A leads to nitrosylation of Myocardin, weakens its effect on promoting the expression of contractile markers and is unable to inhibit the activation of STAT3. These observations reinforce the importance of nitric oxide andS-nitrosylation in angiogenesis and provide a mechanistic pathway for VEGF-A-induced VSMC phenotypic switch. In addition, Myocardin, GSNOR and GSNO can create a negative feedback loop to regulate the VSMC phenotypic switch. Thus, the discovery of this interactive network of signaling pathways provides novel and unexpected therapeutic targets for angiogenesis-dependent diseases.