Fluid shear stress mechanotransduction at endothelial cell-cell junctions

有资金的父母补助金汇总表 我们的项目“内皮细胞-细胞连接处的流体剪切应力机械转导”的目标是 阐明血管内皮细胞感知血流中流体剪切应力（FSS）的机制， 它是血管胚胎发育、成人生理和多种疾病的主要决定因素 包括动脉粥样硬化和血管畸形。虽然有很多途径和基因， FSS已被确定，主要问题的基本分子机制，细胞转换 FSS转化为生化信息仍然没有答案。该项目基于已公布的初步数据 显示细胞-细胞连接是剪切应力机械转导的主要位点，通过复合物 由嗜同性粘附受体PECAM-1（下文称为PECAM）和VE-1组成的膜蛋白。 钙粘蛋白和受体酪氨酸激酶VEGF受体2和3。最近，我们已经确定了 粘附GPCR latrophilin 1（ADGRL 2）作为另一种连接蛋白，似乎是初始上游 触发器激活连接通路[1]。该途径与血管疾病高度相关， PECAM-1的多态性与动脉粥样硬化有关，而ADGRL 2与高血压有关， 缺血性中风

Summary of the funded parent grant The goal of our project “Fluid shear stress mechanotransduction at endothelial cell-cell junctions” is to elucidate mechanisms by which vascular endothelial cells sense fluid shear stress (FSS) from blood flow, which is a major determinant of blood vessel embryonic development, adult physiology and multiple diseases including atherosclerosis and vascular malformations. While a great many pathways and genes that respond to FSS have been identified, major questions about fundamental molecular mechanisms by which cell convert FSS into biochemical information remain unanswered. The project is based on published and preliminary data showing that cell-cell junctions are a major site of shear stress mechanotransduction via a complex of membrane proteins consisting of the homophilic adhesion receptors PECAM-1 (hereafter PECAM) and VE- cadherin, and the receptor tyrosine kinases VEGF receptor 2 and 3. More recently, we have identified the adhesion GPCR latrophilin1 (ADGRL2) as another junctional protein that appears to be the initial upstream trigger that activates the junctional pathway [1]. This pathway is highly relevant to vascular disease as polymorphisms in PECAM-1 are linked to atherosclerosis, while ADGRL2 is linked to hypertension and ischemic stroke.