Voltage-gated L-type Ca²⁺ channel (Ca_v1.2) blockers (LCCBs) are major drugs for treating hypertension, the preeminent risk factor for heart failure. Vascular smooth muscle cell (VSMC) remodeling is a pathological hallmark of chronic hypertension. VSMC remodeling is characterized by molecular rewiring of the cellular Ca²⁺ signaling machinery, including down-regulation of Ca_v1.2 channels and up-regulation of the endoplasmic reticulum (ER) stromal-interacting molecule (STIM) Ca²⁺ sensor proteins and the plasma membrane ORAI Ca²⁺ channels. STIM/ORAI proteins mediate store-operated Ca²⁺ entry (SOCE) and drive fibro-proliferative gene programs during cardiovascular remodeling. SOCE is activated by agonists that induce depletion of ER Ca²⁺, causing STIM to activate ORAI. Here, we show that the three major classes of LCCBs activate STIM/ORAI-mediated Ca²⁺ entry in VSMCs. LCCBs act on the STIM N terminus to cause STIM relocalization to junctions and subsequent ORAI activation in a Ca_v1.2-independent and store depletion-independent manner. LCCB-induced promotion of VSMC remodeling requires STIM1, which is up-regulated in VSMCs from hypertensive rats. Epidemiology showed that LCCBs are more associated with heart failure than other antihypertensive drugs in patients. Our findings unravel a mechanism of LCCBs action on Ca²⁺ signaling and demonstrate that LCCBs promote vascular remodeling through STIM-mediated activation of ORAI. Our data indicate caution against the use of LCCBs in elderly patients or patients with advanced hypertension and/or onset of cardiovascular remodeling, where levels of STIM and ORAI are elevated.

电压门控 L 型 Ca ²⁺通道 (Ca _v 1.2) 阻滞剂 (LCCB) 是治疗高血压的主要药物，而高血压是心力衰竭的首要危险因素。血管平滑肌细胞（VSMC）重塑是慢性高血压的病理标志。VSMC 重塑的特点是细胞 Ca ^{2+信号机制的分子重新布线，包括 Ca} _v 1.2 通道的下调和内质网 (ER) 基质相互作用分子 (STIM) Ca ²⁺传感器蛋白和质膜 ORAI Ca ²⁺通道。STIM/ORAI 蛋白介导钙池操纵的 Ca ²⁺进入 (SOCE) 并在心血管重塑过程中驱动纤维增殖基因程序。SOCE 由诱导 ER Ca ²⁺耗尽的激动剂激活，导致 STIM 激活 ORAI。在这里，我们展示了三大类 LCCB 激活VSMC 中STIM/ORAI 介导的 Ca ^2+进入。LCCB 作用于 STIM N 末端，导致 STIM 重新定位到连接处，并以不依赖于 Ca _v 1.2 和存储耗尽的方式随后激活 ORAI。LCCB 诱导的 VSMC 重塑促进需要 STIM1，STIM1 在高血压大鼠的 VSMC 中表达上调。流行病学表明，与其他抗高血压药物相比，LCCB 与患者心力衰竭的相关性更大。^{我们的研究结果揭示了 LCCB 对 Ca 2+}信号传导的作用机制，并证明 LCCB 通过 STIM 介导的 ORAI 激活促进血管重塑。我们的数据表明，在老年患者或患有晚期高血压和/或心血管重塑的患者中使用 LCCB 需谨慎，因为这些患者的 STIM 和 ORAI 水平升高。