Fibronectin-mediated inflammatory signaling through integrin α5 in vascular remodeling

Abstract

Adhesion of vascular endothelial cells (ECs) to the underlying basement membrane potently modulates EC inflammatory activation. The normal basement membrane proteins laminin and collagen IV attenuate inflammatory signaling in part through integrin 2{beta}1. In contrast, fibronectin, the provisional matrix protein found in injured, remodeling or inflamed vessels, sensitizes ECs to inflammatory stimuli through integrins 5{beta}1and and v{beta}3. A chimeric integrin in which the cytoplasmic domain of 5 is replaced with that of 2 pairs with {beta}1 and binds fibronectin but signals like 2{beta}1. Here, we examined mice in which integrin 5 is replaced with the 5/2 chimera, using the transverse aortic constriction (TAC) and partial carotid ligation (PCL) models of vessel remodeling. Following TAC and PCL surgery, WT mice showed increased fibronectin deposition and expression of inflammatory markers, which were strongly attenuated in a5/2 mice. 5/2 mice also showed reduced artery wall hypertrophy in the TAC model and diminished inward remodeling in the PCL model. Acute atherosclerosis after PCL in hyperlipidemic ApoE-/- mice on a high fat diet was dramatically decreased in 5/2 mice. These results underscore the key role for integrin 5 signaling in pathological vascular remodeling and support its potential as a therapeutic target.