Abstract
Physiological and pathological vascular remodeling is uniquely driven by mechanical forces from blood flow in which wall shear stress (WSS) mechanosensing by the vascular endothelium plays a pivotal role. This study aimed to determine the novel role for a disintegrin and metalloproteinase 17 (ADAM17) in impaired WSS mechanosensing, which was hypothesized to contribute to aging-associated abnormal vascular remodeling. Without changes in arterial blood pressure and blood flow rate, skeletal muscle resistance arteries of aged mice (30-month-old vs. 12-week-old) exhibited impaired WSS mechanosensing and displayed inward hypertrophic arterial remodeling. These vascular changes were recapitulated by in vivo confined, AAV9-mediated overexpression of ADAM17 in the resistance arteries of young mice. An aging-related increase in ADAM17 expression reduced the endothelial junction level of its cleavage substrate, junctional adhesion molecule-A/F11 receptor (JAM-A/F11R). In cultured endothelial cells subjected to steady WSS ADAM17 activation or JAM-A/F11R knockdown inhibited WSS mechanosensing. The ADAM17-activation induced, impaired WSS mechanosensing was normalized by overexpression of ADAM17 cleavage resistant, mutated JAM-AV232Y both in cultured endothelial cells and in resistance arteries of aged mice, in vivo. These data demonstrate a novel role for ADAM17 in JAM-A/F11R cleavage-mediated impaired endothelial WSS mechanosensing and subsequently developed abnormal arterial remodeling in aging. ADAM17 could prove to be a key regulator of WSS mechanosensing, whereby it can also play a role in pathological vascular remodeling in diseases.