缺血训练通过Astrocyte介导的HIF/Wnt信号转导通路促进脑缺血区域血管重塑的机制研究

大量研究表明缺血训练可以促进缺血再灌注脑损伤后神经功能修复。我们前期研究发现缺血训练可通过上调内源性TK表达，促进脑缺血区域血管新生和血流重建，且脑功能的改善与血管新生呈正相关关系。星形胶质细胞作为一种旁分泌细胞，已被证实参与中枢神经系统血管再生过程。前期预实验发现缺血训练上调的内源性TK能激活星形胶质细胞并促进HIF-1α表达。作为调控血管新生的重要因子，HIF-1α可以通过Wnt/β-Catenin信号通路参与血管新生。因此，我们推测缺血训练可调控星形胶质细胞，通过HIF/Wnt通路促进血管内皮细胞增殖、分化，建立侧枝循环，促进血管重塑。为了验证该推测，本项目拟从细胞水平和动物水平，研究缺血训练对星形胶质细胞的调控作用，以及星形胶质细胞介导的HIF/Wnt信号通路促进血管重塑的分子机制。为进一步完善缺血训练对缺血再灌注脑损伤后神经功能恢复提供实验依据。

Numerous studies have indicated that remote ischemic conditioning (IC) could stimulate functional recovery after cerebral ischemia-reperfusion injury. Our previous studies have shown that IC could promote angiogenesis and blood flow in the surrounding ischemic cortex via upregulating endogenous tissue kallikrein (TK)，and neural function outcomes were positively correlated with angiogenesis. As a paracrine cell, astrocytes have been proved to be involved in the angiogenesis of central nervous system. Our preliminary experiments showed that endogenous TK upregulated by IC could activate astrocytes to express HIF-1α, which is an important factor in regulating angiogenesis. The proliferation of endothelial cells is the premise of angiogenesis. Wnt/β-catenin signaling pathway is well known for its role in regulating cell proliferation. It has been confirmed that HIF-1α can regulate Wnt/β-catenin signaling pathway and participate in angiogenesis. Therefore, we hypothesized that IC may regulate astrocytes, promote the proliferation of vascular endothelial cells and promote vascular remodeling via HIF/Wnt pathway. The project will use cell and animal experiments to study the regulation of IC on astrocytes, and the molecular mechanism of astrocyte promote vascular remodeling via HIF/Wnt signaling pathway. The progress of this study is expected to clarify the mechanisms of IC in promoting neural plasticity for ischemic stroke.