Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
Geroscience. 2022 Feb;44(1):349-369. doi: 10.1007/s11357-021-00476-1. Epub 2021 Oct 30.
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 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.
生理和病理血管重塑是由血流产生的机械力独特驱动的，其中血管内皮细胞对壁切应力（WSS）的机械感知起着关键作用。本研究旨在确定解整合素金属蛋白酶 17（ADAM17）在受损的 WSS 机械感知中的新作用，这被假设为导致与衰老相关的异常血管重塑的原因。在不改变动脉血压和血流速度的情况下，老年小鼠（30 月龄与 12 周龄）的骨骼肌阻力动脉表现出受损的 WSS 机械感知，并显示出内向性肥厚性动脉重塑。这些血管变化可以通过在年轻小鼠的阻力动脉中体内限制、AAV9 介导的 ADAM17 过表达来重现。ADAM17 表达的衰老相关增加降低了其裂解底物，连接黏附分子-A/F11 受体（JAM-A/F11R）的内皮连接处水平。在经受稳态 WSS 的培养的内皮细胞中，ADAM17 的激活或 JAM-A/F11R 的敲低抑制了 WSS 机械感知。ADAM17 激活诱导的受损的 WSS 机械感知通过过表达 ADAM17 裂解抗性、突变的 JAM-A 在培养的内皮细胞中和体内老年小鼠的阻力动脉中得到正常化。这些数据表明 ADAM17 在 JAM-A/F11R 裂解介导的受损内皮 WSS 机械感知中具有新的作用，随后在衰老中发展出异常的动脉重塑。ADAM17 可能是 WSS 机械感知的关键调节剂，因此它也可以在疾病中的病理性血管重塑中发挥作用。
