PDGF-BB调控血管平滑肌细胞表型改变的作用及机制研究

Modulation of the vascular smooth-muscle-cell (VSMC) phenotype shifts has been implicated in vascular injury repair and pathogenesis of vascular proliferative diseases. We showed previously that platelet-derived growth factor-BB (PDGF-BB) was elevated in the vascular wall after balloon injury in the rat. PDGF-BB promoted intimal thickening in vivo and inhibited a switch to the contractile phenotype of VSMC in vitro. However, the exact mechanisms of PDGF-BB in mediating VSMC phenotype modulation, as well as proliferative vascular diseases, have not been fully described. It had been demonstrated that miR-26a increased in aortic wall in spontaneously hypertensive rats (SHR). It is unclear whether miR-26a involved in vascular remodeling after balloon injury or not. We will carry out an in vivo gain and loss of function of miR-26a and detect that effect of miR-26a and its target gene on PDGF-BB-mediated VSMC phenotype modulation, cell proliferation, migration, and apoptosis. We will further explore that role and basic mechanism of miR-26a in PDGF-BB-mediated vascular remodeling after balloon injury.

血管平滑肌细胞（VSMC）表型转变是增生性血管病变发生发展的关键环节。前期研究发现，PDGF-BB可抑制VSMC收缩表型标志蛋白的表达，在球囊损伤的大鼠主动脉壁PDGF-BB表达增多，内膜增厚。但是PDGF-BB介导的VSMC表型转变及损伤性血管重塑中的作用及分子机制尚未阐明。本课题组在高血压大鼠血管重塑模型中发现血管壁miR-26a表达增高，我们拟采用PDGF-BB刺激VSMC，研究miR-26a及靶基因对PDGF-BB介导的VSMC表型转换、细胞增殖、迁移、凋亡及细胞外基质分泌等功能的影响，测定VSMC特异性转录因子SRF和辅助激活因子myocardin的表达。在大鼠血管损伤模型中，观察miR-26a对SRF、myocardin表达和血管重塑相关指标的影响，探讨miR-26a在PDGF-BB介导的损伤性血管重塑过程中的调控作用，并阐明其分子机制。

血管平滑肌细胞的表型转化在动脉粥样硬化、血管成形术后再狭窄等多种心血管疾病的发病过程中起关键作用。微小非编码RNA（miRNAs）近年来被证实为调控血管平滑肌细胞的新型分子。本课题综合体外和体内实验证实血小板衍生生长因子-BB（PDGF-BB）可促进血管平滑肌细胞向合成表型转化，miR-26a参与调控这一过程。动脉球囊拉伤后的新生内膜中平滑肌细胞也发生了表型转化，伴有miR-26a表达的上调。我们证实miR-26a可部分逆转PDGF-BB对α肌动蛋白、钙调理蛋白和平滑肌肌球蛋白重链的抑制作用，miR-26a是通过调控靶基因Smad1发挥这一作用的。本研究为探讨PDGF-BB对平滑肌细胞表型转化的作用机制和治疗血管重建后再狭窄提供了研究基础。Smad1是促收缩表型的BMP/TGFβ信号通路中的关键分子，本研究为揭示调控平滑肌细胞表型的PDGF家族和BMP/TGFβ家族的相互作用提供了新的研究思路。项目资助发表SCI论文3篇，待发表3篇。培养博士生1名，已取得博士学位。硕士生3名，其中1名已经取得硕士学位，2名在读。