Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL.
Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL.
J Cell Biol. 2019 Jan 7;218(1):299-316. doi: 10.1083/jcb.201802076. Epub 2018 Nov 21.
Vascular endothelial (VE)-cadherin forms homotypic adherens junctions (AJs) in the endothelium, whereas N-cadherin forms heterotypic adhesion between endothelial cells and surrounding vascular smooth muscle cells and pericytes. Here we addressed the question whether both cadherin adhesion complexes communicate through intracellular signaling and contribute to the integrity of the endothelial barrier. We demonstrated that deletion of N-cadherin () in either endothelial cells or pericytes increases junctional endothelial permeability in lung and brain secondary to reduced accumulation of VE-cadherin at AJs. N-cadherin functions by increasing the rate of VE-cadherin recruitment to AJs and induces the assembly of VE-cadherin junctions. We identified the dual Rac1/RhoA Rho guanine nucleotide exchange factor (GEF) Trio as a critical component of the N-cadherin adhesion complex, which activates both Rac1 and RhoA signaling pathways at AJs. Trio GEF1-mediated Rac1 activation induces the recruitment of VE-cadherin to AJs, whereas Trio GEF2-mediated RhoA activation increases intracellular tension and reinforces Rac1 activation to promote assembly of VE-cadherin junctions and thereby establish the characteristic restrictive endothelial barrier.
血管内皮 (VE)-钙黏蛋白在血管内皮中形成同质黏附连接 (AJ)，而 N-钙黏蛋白在血管内皮细胞和周围的血管平滑肌细胞和周细胞之间形成异质黏附。在这里，我们研究了这两个钙黏蛋白黏附复合物是否通过细胞内信号传递进行通讯，并有助于内皮屏障的完整性。我们证明，内皮细胞或周细胞中 N-钙黏蛋白 ()的缺失会导致肺和脑中的血管通透性增加，这是由于 AJ 处 VE-钙黏蛋白的积累减少。N-钙黏蛋白通过增加 VE-钙黏蛋白在 AJ 处的募集速率并诱导 VE-钙黏蛋白连接的组装来发挥作用。我们确定了双 Rac1/RhoA Rho 鸟嘌呤核苷酸交换因子 (GEF) Trio 作为 N-钙黏蛋白黏附复合物的关键组成部分，它在 AJ 处激活 Rac1 和 RhoA 信号通路。Trio GEF1 介导的 Rac1 激活诱导 VE-钙黏蛋白募集到 AJ，而 Trio GEF2 介导的 RhoA 激活增加细胞内张力并加强 Rac1 激活以促进 VE-钙黏蛋白连接的组装，从而建立特征性的限制内皮屏障。
