After half a century of evidence suggesting the existence of mineralocorticoid receptors (MR) in the vasculature, the advent of technology to specifically knockout the MR from smooth muscle cells (SMCs) in mice has elucidated contributions of SMC-MR to cardiovascular function and disease, independent of the kidney. This review summarizes the latest understanding of the molecular mechanisms by which SMC-MR contributes to (1) regulation of vasomotor function and blood pressure to contribute to systemic and pulmonary hypertension; (2) vascular remodeling in response to hypertension, vascular injury, obesity, and aging, and the impact on vascular calcification; and (3) cardiovascular pathologies including aortic aneurysm, heart valve dysfunction, and heart failure. Data are reviewed from in vitro studies using SMCs and in vivo findings from SMC-specific MR-knockout mice that implicate target genes and signaling pathways downstream of SMC-MR. By regulating expression of the L-type calcium channel subunit Cav1.2 and angiotensin II type-1 receptor, SMC-MR contributes to myogenic tone and vasoconstriction, thereby contributing to systemic blood pressure. MR activation also promotes SMC proliferation, migration, production and degradation of extracellular matrix, and osteogenic differentiation by regulating target genes including connective tissue growth factor, osteopontin, bone morphogenetic protein 2, galectin-3, and matrix metallopeptidase-2. By these mechanisms, SMC-MR promotes disease progression in models of aging-associated vascular stiffness, vascular calcification, mitral and aortic valve disease, pulmonary hypertension, and heart failure. While rarely tested, when sexes were compared, the mechanisms of SMC-MR-mediated disease were sexually dimorphic. These advances support targeting SMC-MR-mediated mechanisms to prevent and treat diverse cardiovascular disorders.

中文翻译：

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血管平滑肌中的盐皮质激素受体：血压及其他

半个世纪以来，有证据表明脉管系统中存在盐皮质激素受体 (MR)，而特异性敲除小鼠平滑肌细胞 (SMC) 中 MR 的技术的出现，阐明了 SMC-MR 对心血管功能和疾病的贡献。独立于肾脏。本综述总结了对 SMC-MR 分子机制的最新认识：(1) 调节血管舒缩功能和血压，从而导致全身性高血压和肺动脉高压； (2) 高血压、血管损伤、肥胖和衰老引起的血管重塑以及对血​​管钙化的影响； (3)心血管疾病，包括主动脉瘤、心脏瓣膜功能障碍和心力衰竭。数据回顾来自使用 SMC 的体外研究和 SMC 特异性 MR 敲除小鼠的体内研究结果，这些结果涉及 SMC-MR 下游的靶基因和信号通路。通过调节 L 型钙通道亚基 Cav1.2 和血管紧张素 II 1 型受体的表达，SMC-MR 有助于肌源性张力和血管收缩，从而有助于全身血压。 MR 激活还通过调节结缔组织生长因子、骨桥蛋白、骨形态发生蛋白 2、半乳糖凝集素 3 和基质金属肽酶 2 等靶基因，促进 SMC 增殖、迁移、细胞外基质的产生和降解以及成骨分化。通过这些机制，SMC-MR 可促进衰老相关血管僵硬、血管钙化、二尖瓣和主动脉瓣疾病、肺动脉高压和心力衰竭模型的疾病进展。虽然很少进行测试，但当比较性别时，发现 SMC-MR 介导的疾病机制具有性别二态性。这些进展支持针对 SMC-MR 介导的机制来预防和治疗多种心血管疾病。