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-A^V232Y 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.

生理和病理性血管重塑独特地由血流机械力驱动，其中血管内皮的壁剪切应力（WSS）机械传感起着关键作用。本研究旨在确定解整合素和金属蛋白酶 17 (ADAM17) 在 WSS 机械传感受损中的新作用，据推测，这种作用会导致与衰老相关的异常血管重塑。在动脉血压和血流速率没有变化的情况下，老年小鼠（30 个月大与 12 周大）的骨骼肌阻力动脉表现出 WSS 机械感应受损，并表现出向内肥厚的动脉重塑。这些血管变化通过体内限制的、AAV9 介导的 ADAM17 在年轻小鼠阻力动脉中的过度表达来重现。与衰老相关的 ADAM17 表达增加降低了其裂解底物、连接粘附分子-A/F11 受体 (JAM-A/F11R) 的内皮连接水平。在培养的内皮细胞中，WSS ADAM17 稳定激活或 JAM-A/F11R 敲低会抑制 WSS 机械传感。 ADAM17 激活诱导的、受损的 WSS 机械传感通过在体内培养的内皮细胞和老年小鼠的阻力动脉中过度表达 ADAM17 裂解抗性、突变的 JAM-A ^V232Y来正常化。这些数据证明 ADAM17 在 JAM-A/F11R 裂解介导的内皮 WSS 机械传感受损以及随后在衰老过程中发生异常动脉重塑中发挥着新作用。 ADAM17 可能被证明是 WSS 机械传感的关键调节因子，因此它还可以在疾病的病理性血管重塑中发挥作用。