Gab1介导的机械性信号转导在血管重塑中的作用及其机制

Vascular remodeling is a process in which the vascular wall significantly thickens with functional alterations as a result of vascular injuries caused by a variety of factors including mechanical stress. So far, its underlying molecular mechanisms remain incompletely understood. Previously, we reported for the first time that Gab1, an important signal adaptor, plays a critical role in mouse hindlimb ischemic angiogenesis and tissue repair, which has been confirmed later by other groups. Recently, we found that mechanical stretch rapidly induced Gab1 phosphorylation and intracellular translocation from cytoplasm to membrane in cultured endothelial cells. Furthermore, we showed that compared to wild type mice, endothelium-specific Gab1 knockout mice displayed a defect in vascular remodeling with thin adventitia and severe splenomegaly in response to portal vein hypertension generated by partial portal vein ligation. These data suggest that Gab1 may play a role in vascular remodeling induced by mechanical stress. In this application, except for portal vein hypertension-induced venous remodeling, we will also examine the roles of Gab1 in flow-mediated carotid artery remodeling and autologous grafted vein remodeling in which the external jugular veins are grafted end to end into carotid arteries. We will study cellular mechanism of vascular cells involved and define the cascades of Gab1 signaling pathways in vascular cells under mechanical stresses. This study will not only add new insight into the understanding of vascular remodeling at early adaptive stage, but may provide potential new targets for the prevention and treatment of related diseases.

血管重塑是血管壁在受到包括生物力学因素在内的多种刺激下产生的结构性和功能性改变，其分子机制尚不完全清楚。Gab1是一个重要的信号接头分子，我们先前曾首次报道Gab1介导的信号通路诱导缺血性血管新生，促进组织损伤修复。最近我们还发现，机械性牵拉刺激可以激活血管内皮细胞的Gab1分子，引起Gab1快速磷酸化及由胞浆转位上膜；并发现，与野生型小鼠相比Gab1的内皮细胞特异性敲除小鼠门静脉出现高血压性血管重塑障碍，表现为外膜变薄，脾脏肿大加重。这些结果提示Gab1可能在生物力学因素关联血管重塑的早期适应性过程中起重要作用。本课题除门静脉高血压性血管重塑外，还将研究Gab1在动脉血流改变诱导血管重塑和自体移植静脉血管重塑中的作用，探讨Gab1介导的机械性信号转导途径，及其具体的细胞和分子机制。本课题不仅能加深对血管重塑早期适应性阶段细胞和分子机制的了解，还将为血管重塑相关疾病的防治找到新的靶点。

Gab1是细胞信号传导接头平台分子的家族成员，在血管内皮细胞力学信号转导过程中起一定的作用。运用基因敲除小鼠及血管重塑模型，我们发现：1）血管内皮Gab1基因缺失显著减弱血管重塑，伴随内膜结构细胞组分的差异；2）血管内皮Gab1基因缺失引起的血管重塑异常与早期血管内皮炎症反应异常有关；3）分子机制研究表明，Gab1、myosin IIa、Zyxin等同属于信号蛋白质复合物；4）进一步使用zyxin基因敲除小鼠证实，Zyxin基因缺失导致血管损伤稳态反应减弱。总之，通过本项目研究，我们发现了血管稳态维持的关键信号通路和分子，为进一步研究血管稳态的防御机制，及病理状态下的分子干预提供了重要基础。