LRRC8A氯通道下调促进血管新生改善缺血性疾病的作用及机制

我们发现胞内氯离子浓度降低可抑制VEGF诱导VEGF/VEGFR2信号通路活化，进而抑制内皮细胞迁移和管腔形成。而VEGF则抑制低氯环境下细胞内氯离子往胞外转运的过程并减少LRRC8A氯通道的表达。下调LRRC8A可促进内皮细胞迁移和管腔形成，并改善心肌梗死小鼠心功能，提示其可能是调控血管新生的关键因素。本研究拟在前期工作的基础上，采用LRRC8A内皮特异性敲除和转基因小鼠，制备心肌梗死和后肢缺血模型，明确其对血管新生和缺血性组织损伤的影响，并进一步阐明LRRC8A氯通道介导的胞内氯离子浓度变化是调控血管新生的关键作用机理。本研究工作将较为系统地明确LRRC8A对血管新生和缺血性疾病的调控作用，并揭示LRRC8A调控VEGF/VEGFR2信号通路的具体分子机制，为评估LRRC8A是否可作为防治冠心病等缺血性疾病的新靶点提供实验室依据。

Recent studies have demonstrated that lowering of serum chloride (Cl−) is an independent predictor of mortality in hypertensive patients, but the underlying mechanisms remain unknown. Our previous work demonstrates that reduction of intracellular Cl− concentration ([Cl−]i) attenuated VEGF-induced cell migration and tube formation in endothelial cells via inhibition of VEGF/VEGFR2 signaling pathway. We further found that VEGF decreased LRRC8A expression. Inhibition of LRRC8A promoted endothelial cell migration and tube formation and prevented cardiac injury in myocardial infarction model of mice, suggesting LRRC8A-mediated Cl− efflux may play a critical role in regulating angiogenesis. The present study aims to clarify the functional role of LRRC8A in angiogenesis and ischemic tissue injury of myocardial infarction and limb ischemia experimental model with LRRC8A endothelium-specific knockout mice. Furthermore, we will investigate how LRRC8A-mediated the changes of [Cl−]i influences angiogenesis. These findings will evidence the important function of LRRC8A in angiogenesis and ischemic diseases and uncover the precise molecular mechanisms by which LRRC8A regulates VEGF/VEGFR2 pathway, indicating LRRC8A may be a novel therapeutic target for the treatment of ischemic diseases.