Stiffening of the vasculature with aging is a strong predictor of adverse cardiovascular events, independent of all other risk factors including blood pressure, yet no therapies target this process. MRs (mineralocorticoid receptors) in smooth muscle cells (SMCs) have been implicated in the regulation of vascular fibrosis but have not been explored in vascular aging. Comparing SMC-MR-deleted male mice to MR-intact littermates at 3, 12, and 18 months of age, we demonstrated that aging-associated vascular stiffening and fibrosis are mitigated by MR deletion in SMCs. Progression of cardiac stiffness and fibrosis and the decline in exercise capacity with aging were also mitigated by MR deletion in SMC. Vascular gene expression profiling analysis revealed that MR deletion in SMC is associated with recruitment of a distinct antifibrotic vascular gene expression program with aging. Moreover, long-term pharmacological inhibition of MR in aged mice prevented the progression of vascular fibrosis and stiffness and induced a similar antifibrotic vascular gene program. Finally, in a small trial in elderly male humans, short-term MR antagonism produced an antifibrotic signature of circulating biomarkers similar to that observed in the vasculature of SMC-MR-deleted mice. These findings suggest that SMC-MR contributes to vascular stiffening with aging and is a potential therapeutic target to prevent the progression of aging-associated vascular fibrosis and stiffness.

Changes in cardiorespiratory fitness in response to a standardized exercise training protocol differ substantially between individuals. Results from cross-sectional, twin, and family studies indicate genetics contribute to individual differences in both baseline exercise capacity and the response to training. Exercise capacity and responses to training also vary between inbred strains of mice. However, such studies have utilized a limited number of inbred strains. Therefore, the aim of this study was to characterize exercise-training responses in a larger number of genetically diverse strains of inbred mice and estimate the contribution of genetic background to exercise training responses. Eight-week old male mice from 24 inbred strains (n = 4–10/strain) performed a graded exercise test before and after 4 weeks of exercise training. Before training, exercise capacity was significantly different between strains when expressed as time (range = 21–42 min) and work performed (range = 0.42–3.89 kg·m). The responses to training also were significantly different between strains, ranging from a decrease of 2.2 min in NON/ShiLtJ mice to an increase of 8.7 min in SWR/J mice. Changes in work also varied considerably between the lowest (−0.24 kg·m in NON/ShiLtJ) and highest (+2.30 kg·m in FVB/NJ) performing strains. Heart and skeletal muscle masses also varied significantly between strains. Two broad sense heritability estimates were calculated for each measure of exercise capacity and for responses to training. For change in run time, the intraclass correlation between mice within the same inbred strain (rI) was 0.58 and the coefficient of genetic determination (g2) was 0.41. Heritability estimates were similar for the change in work: rI = 0.54 and g2 = 0.37. In conclusion, these results indicate genetic background significantly influences responses to exercise training.

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.