VEGF影响转录因子Stat3和myocardin调节血管平滑肌细胞表型转换的分子机制

Vascular endothelial growth factor (VEGF) can induce the proliferation and migration of vascular endothelial cells, and then promote angiogenesis. But, there is little studies about the role of VEGF with vascular smooth muscle cells (VSMCs). During the pathological process of vascular injury, differentiated SMCs transform to proliferative type. Myocardin, a strong co-transcriptional factor of serum response factor (SRF), is interacted with SRF, and then induce SMCs differentiating. As well as signal transduction and activator of transcription factor -3 (Stat3) inhibits the differentiation and promotes the conversion of SMCs from a differentiated to proliferative, and SRF and Stat3 both can induce the expression of VEGF. We previously demonstrated the myocardin and Stat3 can directly interact with each other. On this base, the study will prove how VEGF regulates transcription factors of Stat3 and myocardin-SRF, thereby affecting SMC differentiation and proliferation phenotype conversion, and clarify the lastest molecular mechanism of transcriptional regulation about SMCs phenotype conversion.

血管内皮细胞生长因子（VEGF）能够诱导血管内皮细胞增殖和迁移，促进血管生成。但其对血管平滑细胞（VSMCs）作用研究甚少。SMCs在血管损伤病理过程中，由分化型向增殖型转换。血清反应因子（SRF)强力辅助转录因子Myocardin通过与SRF相互作用可诱导SMCs分化，而信号转导和转录激活因子-3（Stat3)则发挥抑制SMCs分化，促进SMCs由分化型向增殖型转换，且SRF和Stat3均能诱导VEGF表达。我们在先前证明Myocardin和Stat3能够直接蛋白-蛋白作用基础上，拟利用各种细胞分子生物学手段，证明VEGF如何对Stat3和Myocardin-SRF转录因子调控，进而影响SMC分化和增殖表型转换，阐明SMCs表型转换过程中最新转录调控分子机制，为防治动脉粥样硬化提供基础理论。

缝隙连接蛋白43（Connexin43，CX43）调控血管平滑肌细胞（VSMC）的增殖过程中具有重要作用，myocardin是调控VSMCs分化的关键因子，miR-206是平滑肌细胞增殖的重要调控因子。那么myocardin、miR-206和CX43转录因子网络如何相互作用，影响VSMC分化与增殖？这种作用的分子机制如何？对AS疾病模型的具体作用又如何？对平滑肌细胞增殖相关基因转录因子网络的研究具有创新性，旨在找到亟待解决的动脉粥样硬化相关的基础问题的突破点。本文围绕myocardin/miR-206/connexin43通路在VSMCs增殖及对动脉粥样硬化疾病的作用展开了深入的研究。本研究围绕myocardin/miR-206/CX43信号通路作用于HA-VSMCs增殖分化展开深入研究，发现其具有抑制增殖及表型转换的作用。miR-206在转录后水平下调CX43的蛋白表达，从而抑制HA-VSMCs细胞增殖及表型转换。过表达myocardin可有效下调血管平滑肌细胞增殖水平，抑制血管平滑肌细胞向增殖表型转换。体内实验表明miR-206可有效缩小动脉粥样斑块面积及胶原纤维沉积，延缓疾病进展，有效下调血管组织中的CX43蛋白水平，且伴随动脉粥样硬化斑块的缩小。另外还发现在ApoE-/-小鼠模型中过表达miR-206降低小鼠血清总胆固醇水平，上调高密度脂蛋白水平，具有防治动脉粥样硬化疾病的潜在价值。 Myocardin、miR-206调控缝隙连接蛋白的作用，这对防治慢性血管性疾病的研究具有重要意义。