The Mechanosensation-Metabolism-Inflammation Axis: The Central Role of Piezo1 and TRPV4 in Hypertension-Related Atherosclerosis

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Ying-Ying Mu,1,2 Ting-Ting Liu,1 Jie-Lei Xu,1 Peng-Cheng Li,1 Yue Qian,3 Wei Zhang1 1Medical Affairs Department, the second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, People’s Republic of China; 2Department of Pathology, Zunyi Hospital of Traditional Chinese Medicine, Zunyi, Guizhou, 563000, People’s Republic of China; 3Department of Pathogen Biology, Guizhou Nursing Vocational College, Guiyang, Guizhou, 550000, People’s Republic of ChinaCorrespondence: Yue Qian, Department of Pathogen Biology, Guizhou Nursing Vocational College, Guiyang, Guizhou, 550000, People’s Republic of China, Email gznvc_qianyue@163.com Wei Zhang, Medical Affairs Department, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, People’s Republic of China, Email zunyi_zhangwei@163.comAbstract: Atherosclerosis is a core independent risk factor for cardiovascular events. The abnormal hemodynamic microenvironment mediated by hypertension is a key initiating factor for its development and progression, and mechanosensitive ion channels are the core molecules connecting vascular mechanical forces to intracellular biochemical signals. Piezo1 and Transient Receptor Potential Vanilloid 4 (TRPV4), as important mechanosensitive ion channels in blood vessels, are widely expressed in vascular endothelial cells, smooth muscle cells, and immune cells. They can sense and be activated by abnormal circumferential stress and shear stress under hypertensive conditions. This review systematically synthesizes current evidence to test the central hypothesis that Piezo1 and TRPV4 form a functionally synergistic signaling axis, converting pathological mechanical forces into sustained Ca2⁺ influx, which subsequently drives an integrated network of metabolic imbalance and chronic inflammation in hypertension-related atherosclerosis. It focuses on the activation modes of these channels by abnormal mechanical forces in hypertension and the subsequent early Ca2⁺ signaling dysregulation. The regulatory pathways of channel-mediated lipid and glucose metabolism disorders are deeply analyzed. The specific mechanisms by which both channels participate in the regulation of endothelial dysfunction, inflammatory infiltration, foam cell formation, and plaque stability in atherosclerosis through key signaling pathways such as NF-κB, NLRP3, and YAP/TAZ are comprehensively summarized. Furthermore, intervention strategies using natural compounds targeting this channel axis are discussed. Research indicates that Piezo1 and TRPV4 form a functionally synergistic signaling axis. By converting abnormal mechanical forces into sustained Ca2⁺ influx, they drive metabolic imbalance and chronic inflammation in vascular cells, realizing a functional transition from physiological protection to pathological damage. The cell-specific, environment-dependent regulatory characteristics and the bidirectional interaction network of these two channels constitute an important pathological regulatory mechanism for hypertension-related atherosclerosis. This review aims to establish a complete regulatory network of “mechanosensation-ion channel-calcium signal-metabolic inflammation-atherosclerosis” and provide an integrated framework for clarifying the molecular mechanisms of hypertension-associated atherosclerosis, and exploring potential targets and intervention strategies for the precise prevention and treatment of the disease.Keywords: Piezo1, TRPV4, mechanosensitive ion channel, hypertension, atherosclerosis, calcium signal, metabolic disorder, vascular remodeling

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