Sex differences in molecular mechanisms of vascular aging

Hypertension (HTN) is the most prevalent cardiovascular disease risk factor. Although HTN incidence rises profoundly with age in both sexes, females are relatively protected when they are young and after menopause, females ultimately exceed males in the incidence and adverse outcomes of HTN. In male mice with SMC‐specific deletion of the mineralocorticoid receptor (MR‐KO), we showed protection from the aging‐associated rise in blood pressure (BP). We show that in males, the mechanism involves SMC‐MR transcriptionally repressing vascular miR‐155 expression with age, 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). Further studies revealed that restoration of SMC‐specific miR‐155 rescues the aging phenotype observed in male mice. Specifically, raising SMC‐miR‐155 expression resulted in decreased Cav1.2 and AT1R expression and LTCC‐and AT1R‐mediated vasoconstriction. In female mice, however, Cav1.2 and AT1R expression did not change with age. Additionally, vasoconstriction to LTCC agonist BayK‐8644 and Ang II are not increased in aging females compared to young females. These results suggest that mechanism of vascular aging and BP control are distinct between males and females. These data support that sex‐specific therapies may be beneficial in managing vascular aging and BP control. Support or Funding Information Supported by HL095590‐05, HL119290, and 15POST213.