Role of ADAMs in Endothelial Cell Permeability

Abstract

See related article, pages 1192–1201 Endothelial cells constitute a selective barrier that controls the passage of plasma proteins and circulating cells from the blood to tissues. This is achieved by the caveolar–vesicular system and by the dynamic opening and closing of intercellular junctions.1 Interendothelial cell junctions are almost absent in the postcapillary venules, where cellular extravasation and exchange of plasma constituents occur, but are well-organized in the large vessels to ensure strict control of vascular permeability. Cadherins are Ca2+- and protease-sensitive molecules that mediate homotypic cell-to-cell adhesion. Endothelial cells express N-, P-, and VE-cadherin. N-cadherin is diffusely spread on the cell surface, whereas P-cadherin is present in trace amounts. VE-cadherin is a single-chain transmembrane glycoprotein localized at specialized interendothelial cell contact regions referred to as adherens junctions.2 Vascular inflammation has been implicated in the development and progress of vascular diseases such as hypertension and atherosclerosis.3 The inflammatory response is initiated by injury of the endothelium inflicted by factors such as oxidized low-density lipoprotein, reactive oxygen species, and viruses. Endothelial cell injury prompts the recruitment of circulating leukocytes to the injury site, and the disruption of the endothelial cell barrier allows leukocyte infiltration of the vessel wall (Figure). Leukocyte recruitment and infiltration of the vascular wall is a complex process encompassing a series of adhesion and deadhesion events and distinct adhesion molecules on the activated endothelium and leukocytes. Figure. Role of ADAM-10 in leukocyte recruitment and transmigration and endothelial cell permeability. In activated endothelium, upregulated cell adhesion molecules such as fractalkine, CXCL16, and hyaluronan (![Graphic][1] ) bind their respective receptors CX3CR1, CXCR6, and CD44 (![Graphic][2] ), resulting in initial capture of inflammatory cells. Inflammatory mediators, such as thrombin (acting via protease-activated receptor [PAR]), and leukocyte adhesion increase endothelial cell [Ca2+]i, causing the release of pro–ADAM-10 … [1]: F1/embed/inline-graphic-1.gif [2]: F1/embed/inline-graphic-2.gif