Sex differences in the role of the smooth muscle cell mineralocorticoid receptor in cardiovascular aging
Authors: DuPont Jennifer J. , Kim Seung K. , Sun Zhe , Aronovitz Mark J. , Baur Wendy E. , Meininger Gerald A. , Hill Michael A. , Jaffe Iris Z. 
Published: June 2021

Vascular aging is a process that involves the development of vasomotor dysfunction and vessel stiffening, which leads to cardiovascular disease (CVD). Clinical data supports that differential mechanisms may be involved in the progression of vascular aging in males compared to females. We have previously demonstrated that male mice with smooth muscle cell (SMC)‐specific deletion of the mineralocorticoid receptor (MR‐KO), a steroid hormone receptor known to regulate renal sodium handling, have lower blood pressure, vascular tone, and vasoconstriction as they age. The purpose of this study was to determine whether there are sex differences in the role of SMC‐MR in vascular aging. We demonstrated that vascular MR expression increases and miR‐155 decreases from 3 to 12 months of age in male mice. Additional studies revealed that SMC‐MR transcriptionally represses vascular miR‐155, which then promotes an increase in expression of miR‐155 target genes, Cav1.2, the pore‐forming subunit of the L‐type calcium channel (LTCC) and the angiotensin II type 1 receptor (AT1R) at 12 months of age in male mice. When compared directly to males, aging female mice do not display an increase in vascular MR expression until 18 months of age, accompanied by a decrease in miR‐155. Similarly, 12 month old female mice do not have altered vascular expression of Cav1.2 or AT1R compared to young females. Further, LTCC function is increased at 12 months of age in males and decreased at 12 months of age in females and then ultimately rose in females by 18 months of age. Additionally, Ang II‐mediated vasoconstriction increases at 12 months of age in males and is attenuated by SMC‐MR‐KO, however, in females, Ang II constriction is unaltered at 12 months of age and then surpasses the male Ang II constriction response at 18 months of age. We also observed an increase in vascular stiffness, measured by aortic pulse wave velocity, in male mice at 12 months of age that persists at 18 months of age and is prevented by SMC‐MR‐KO. In contrast, female mice do not exhibit increases in stiffness until 18 months of age, which is also attenuated by SMC‐MR‐KO. To explore potential mechanisms of vascular stiffness, we performed atomic force microscopy studies in 16–19 month old male and female mice. Females exhibited significantly more SMC‐stiffness than males, and SMC‐MR‐KO partially restored the aging‐associated stiffness. We also examined cardiac function, measured by echocardiography, and found that systolic and diastolic cardiac function declines with age in both males and females, but is modulated by SMC‐MR‐KO in females only. Further, we found that exercise capacity, measured by a graded exercise test, declines in both males and females with age, but is modulated by SMC‐MR‐KO in males only. Together, these results suggest that the mechanisms and time course of cardiovascular aging are distinct between males and females, and that SMC‐MR appears to play a differential role in males versus females. Furthermore, these studies suggest that sex‐specific therapies may be essential to improve CVD outcomes in the aging population.Support or Funding InformationSupported by HL095590‐05, HL119290, and AHA15POST21300000.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.