Cronin Nicholas M, Dawson Logan W, DeMali Kris A
Roy J. and Lucille A. Carver College of Medicine at the University of Iowa, Department of Biochemistry and Molecular Biology, 51 Newton RD, Iowa City, IA 52242.
bioRxiv. 2024 May 13:2024.05.09.593171. doi: 10.1101/2024.05.09.593171.
Endothelia cells respond to mechanical force by stimulating cellular signaling, but how these pathways are linked to elevations in cell metabolism and whether metabolism supports the mechanical response remains poorly understood. Here, we show that application of force to VE-cadherin stimulates liver kinase B1 (LKB1) to activate AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis. VE-cadherin stimulated AMPK increases eNOS activity and localization to the plasma membrane as well as reinforcement of the actin cytoskeleton and cadherin adhesion complex, and glucose uptake. We present evidence for the increase in metabolism being necessary to fortify the adhesion complex, actin cytoskeleton, and cellular alignment. Together these data extend the paradigm for how mechanotransduction and metabolism are linked to include a connection to vasodilation, thereby providing new insight into how diseases involving contractile, metabolic, and vasodilatory disturbances arise.
内皮细胞通过刺激细胞信号传导来响应机械力，但这些信号通路如何与细胞代谢的升高相关联，以及代谢是否支持机械反应仍知之甚少。在这里，我们表明对血管内皮钙黏蛋白施加力会刺激肝激酶B1（LKB1）激活AMP激活的蛋白激酶（AMPK），这是能量稳态的主要调节因子。血管内皮钙黏蛋白刺激的AMPK增加内皮型一氧化氮合酶（eNOS）的活性及其在质膜上的定位，以及肌动蛋白细胞骨架和钙黏蛋白黏附复合物的强化，还有葡萄糖摄取。我们提供证据表明代谢的增加对于加强黏附复合物、肌动蛋白细胞骨架和细胞排列是必要的。这些数据共同扩展了机械转导与代谢如何联系的范例，以包括与血管舒张的联系，从而为涉及收缩、代谢和血管舒张紊乱的疾病如何产生提供了新的见解。
