A functional coupling of TRPA1 and TMEM16A channels regulates endothelium-dependent hyperpolarization-mediated vasorelaxation of mesenteric arterioles in healthy and septic mice

作者：Yanan Zhang, Shaya Rong, Shude Pang, Xiujun Fu, Yunxian Wang, Xuelu Ding, Shuai Liang, Ruihong Guo, Hui Dong · 年份：2025 · DOI：10.22541/au.176355582.28202586/v1 · 研究领域：Ion Channels and Receptors、Gastrointestinal motility and disorders、Nitric Oxide and Endothelin Effects

Background and Purpose: Impairment of the vascular endothelium plays a crucial role in exacerbating sepsis and precipitating multi-organ failure. Although TRPA1 and TMEM16A channels are expressed in vascular system, the precise mechanisms underlying TRPA1- and TMEM16A-mediated arteriolar vasorelaxation in health and their involvement in sepsis remain largely unclear. Experimental Approach: The vasorelaxant effects of TRPA1 and TMEM16A on the second-order branch of mesenteric arterioles were investigated in healthy and septic mice using a Mulvany-style wire myograph. Fluorescent Ca 2+ assays were employed to assess cytosolic Ca 2+ ([Ca 2+ ] i ) in vascular endothelial cells (VECs). A mouse sepsis model was constructed through the method of cecal ligation and puncture (CLP). The HPLC-MS/MS technique was employed to determine the plasma concentrations of TRPA1 and TMEM16A agonists in mice. Key Results: Activation of either TRPA1 or TMEM16A channels induced vasorelaxation of mesenteric arterioles via endothelium-dependent hyperpolarization (EDH) mechanisms predominately. Moreover, a functional coupling of TRPA1 and TMEM16A channels was identified in EDH-mediated vasorelaxation. TRPA1 activation induced Ca 2+ influx into VECs, which further amplified intracellular Ca 2+ release via the Ca 2+ -induced Ca 2+ release mechanism. During sepsis, while ACh/EDH-mediated vasorelaxation was largely impaired, TRPA1/TMEM16A/EDH-mediated vasorelaxation remained intact. Notably, activation of T...