Aging is associated with heart and vascular dysfunction that contributes to cardiovascular disease (CVD) risk. Clinical data support a sexual dimorphism in the time course of aging-associated CVD. However, the mechanisms driving sex differences in cardiovascular aging and whether they can be modeled in mice has not been explored. Mineralocorticoid receptors (MR) regulate blood pressure and we previously demonstrated in male mice that MR expression increases in aging mouse vessels and smooth muscle cell-specific MR deletion (SMC-MR-KO) protects from cardiovascular aging. This study characterizes sex differences in murine cardiovascular aging and the associated sex-specific role of SMC-MR. Aortic stiffness, measured by pulse wave velocity, increased from 3 to 12 months of age in males but not until 18 months in females. The timing of the rise in aortic stiffening correlated with the timing of increased aortic MR expression and aortic stiffness did not increase with age in SMC-MR-KO mice of both sexes. Vascular fibrosis increased at 12 months in males and later at 18-months in females; however, fibrosis was attenuated by SMC-MR-KO in males only. In resistance vessels, angiotensin type 1 receptor (AT1R)-mediated vasoconstriction also increased at 12-months in males and 18-months in females. AngII-induced vasoconstriction was decreased in SMC-MR-KO only in males in association with decreased AT1R expression. Cardiac systolic function declined in males and females by 18-months of age, which was prevented by SMC-MR-KO specifically in females. Cardiac perivascular fibrosis increased with age in both sexes accompanied by sex-specific changes in the expression levels of MR-regulated pro-fibrotic genes.

中文翻译：

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小鼠血管和心脏衰老时间过程和机制的性别差异：平滑肌细胞盐皮质激素受体的作用


衰老与心脏和血管功能障碍有关，从而增加心血管疾病 (CVD) 的风险。临床数据支持与衰老相关的 CVD 的时间过程中存在性别二态性。然而，驱动心血管衰老性别差异的机制以及是否可以在小鼠中建立模型尚未得到探索。盐皮质激素受体 (MR) 调节血压，我们之前在雄性小鼠中证明，衰老小鼠血管中 MR 表达增加，平滑肌细胞特异性 MR 缺失 (SMC-MR-KO) 可防止心血管衰老。本研究描述了小鼠心血管衰老的性别差异以及 SMC-MR 的相关性别特异性作用。通过脉搏波速度测量，男性的主动脉僵硬度从 3 个月到 12 个月大时有所增加，但女性要到 18 个月大时才会增加。在两种性别的 SMC-MR-KO 小鼠中，主动脉僵硬增加的时间与主动脉 MR 表达增加的时间相关，并且主动脉僵硬度不随年龄而增加。男性的血管纤维化在 12 个月时增加，女性则在 18 个月时增加；然而，SMC-MR-KO 仅在男性中减弱了纤维化。在阻力血管中，12 个月大的男性和 18 个月大的女性中，血管紧张素 1 型受体 (AT1R) 介导的血管收缩也有所增加。 SMC-MR-KO 中 AngII 诱导的血管收缩仅在男性中减少，与 AT1R 表达减少相关。男性和女性的心脏收缩功能在 18 个月大时下降，而 SMC-MR-KO 可以预防这种情况，特别是在女性中。男女心脏血管周围纤维化均随着年龄的增长而增加，并伴有 MR 调节的促纤维化基因表达水平的性别特异性变化。