Cardiovascular disease remains the leading cause of death for both men and women. The observation that premenopausal women are protected from cardiovascular disease relative to age-matched men, and that this protection is lost with menopause, has led to extensive study of the role of sex steroid hormones in the pathogenesis of cardiovascular disease. However, the molecular basis for sex differences in cardiovascular disease is still not fully understood, limiting the ability to tailor therapies to male and female patients. Therefore, there is a growing need to investigate molecular pathways outside of traditional sex hormone signaling to fully understand sex differences in cardiovascular disease. Emerging evidence points to the mineralocorticoid receptor (MR), a steroid hormone receptor activated by the adrenal hormone aldosterone, as one such mediator of cardiovascular disease risk, potentially serving as a sex-dependent link between cardiovascular risk factors and disease. Enhanced activation of the MR by aldosterone is associated with increased risk of cardiovascular disease. Emerging evidence implicates the MR specifically within the endothelial cells lining the blood vessels in mediating some of the sex differences observed in cardiovascular pathology. This review summarizes the available clinical and preclinical literature concerning the role of the MR in the pathophysiology of endothelial dysfunction, hypertension, atherosclerosis, and heart failure, with a special emphasis on sex differences in the role of endothelial-specific MR in these pathologies. The available data regarding the molecular mechanisms by which endothelial-specific MR may contribute to sex differences in cardiovascular disease is also summarized. A paradigm emerges from synthesis of the literature in which endothelial-specific MR regulates vascular function in a sex-dependent manner in response to cardiovascular risk factors to contribute to disease. Limitations in this field include the relative paucity of women in clinical trials and, until recently, the nearly exclusive use of male animals in preclinical investigations. Enhanced understanding of the sex-specific roles of endothelial MR could lead to novel mechanistic insights underlying sex differences in cardiovascular disease incidence and outcomes and could identify additional therapeutic targets to effectively treat cardiovascular disease in men and women.

中文翻译：

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内皮盐皮质激素受体：心血管疾病性别差异的贡献。


心血管疾病仍然是男性和女性死亡的主要原因。观察发现，与同龄男性相比，绝经前女性可以免受心血管疾病的侵害，而这种保护作用会随着更年期而消失，这导致了对性类固醇激素在心血管疾病发病机制中的作用的广泛研究。然而，心血管疾病性别差异的分子基础仍未完全了解，限制了针对男性和女性患者定制治疗的能力。因此，越来越需要研究传统性激素信号传导之外的分子途径，以充分了解心血管疾病的性别差异。新的证据表明，盐皮质激素受体（MR）是一种由肾上腺激素醛固酮激活的类固醇激素受体，是心血管疾病风险的调节因子之一，可能是心血管风险因素与疾病之间的性别依赖性联系。醛固酮增强 MR 激活与心血管疾病风险增加相关。新出现的证据表明，血管内皮细胞内的 MR 介导了心血管病理学中观察到的一些性别差异。本综述总结了有关 MR 在内皮功能障碍、高血压、动脉粥样硬化和心力衰竭的病理生理学中的作用的现有临床和临床前文献，特别强调内皮特异性 MR 在这些病理中的作用的性别差异。还总结了有关内皮特异性 MR 可能导致心血管疾病性别差异的分子机制的现有数据。 综合文献得出一个范例，其中内皮特异性 MR 以性别依赖性方式调节血管功能，以响应导致疾病的心血管危险因素。该领域的局限性包括临床试验中女性相对较少，以及直到最近，临床前研究中几乎只使用雄性动物。增强对内皮细胞MR的性别特异性作用的理解可能会导致对心血管疾病发病率和结果的性别差异的新机制的认识，并可能确定有效治疗男性和女性心血管疾病的其他治疗靶点。