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.