Role of ADAM17 in Aging‐induced Vascular Remodeling of Skeletal Muscle Resistance Arteries

Abstract

Aging-induced abnormal remodeling of small resistance arteries is poorly understood. Increasing in blood flow and wall shear stress (WSS) induces outward remodeling, whereas reduction in WSS causes lumen narrowing inward vascular remodeling. We hypothesized that impaired wall shear stress (WSS) sensing by the vascular endothelium plays a key role in aging-related vascular remodeling. In aged mice (30-month vs. 12-week old), perfused and pressurized skeletal muscle resistance arteries showed increased disintegrin and metalloproteinase 17 (ADAM17) expression and decreased endothelial junction level of its cleavage substrate, junctional adhesion molecule-A/F11 receptor (JAM-A/F11R). By using videomicroscopy of isolated, perfused skeletal muscle arteries from young and aged mice, we observed that aging impaired WSS mechanosensing, reduced WSS-induced vasodilation, and caused inward hypertrophic arterial remodeling. These changes were recapitulated by in vivo confined arterial AAV9-mediated delivery of ADAM17 in young mice. In vitro, activation of ADAM17 in endothelial cells subjected to steady WSS reduced junction-localized JAM-A/F11R, whereas JAM-A/F11R knockdown or ADAM17 activation inhibited WSS-dependent cell alignment, which was normalized by overexpression of ADAM17 cleavage resistant, mutated JAM-AV232Y. These data demonstrate a novel role for ADAM17 in aging-related resistance artery remodeling via JAM-A/F11R cleavage-mediated, impaired WSS mechanosensing.