Sex differences in the role of the vascular angiotensin II receptors in vascular aging
Authors: DuPont Jennifer J. , Kenney Rachel M. , Kim Seung K. , Baur Wendy , Lu Qing , Martin Gregory , Pulakat Lakshmi 
Published: April 2020

Background

Aged women have greater vascular stiffness and vasomotor dysfunction vs. aged men, leading to a greater incidence of cardiovascular disease (CVD). However, the underlying mechanisms that mediate these differences are unclear. The hormone angiotensin II promotes vascular aging via the AngII type 1 receptor (AT1R). However, AngII also acts through the AngII type 2 receptor (AT2R), which is vasoprotective. Previous studies report sex and age‐related differences in AT2R function in the kidney. However, the role for the AT2R in male and female vascular aging is unknown.

Methods/Results

All studies were conducted in accordance with the FASEB Statement of Principles for the use of Animals in Research and Education. We measured aortic pulse wave velocity, an index of vascular stiffness, in 3,12, and 18 month old male and female C57/Bl6 mice. Our results show that males develop increases in vascular stiffness from 3 to 12 months compared to 3 to 18 months in females (p<0.05). To determine the potential role of the AT2R in the vascular protection observed in 12 month old female mice, we treated 12 and 18 month old male and female mice with AT2R antagonist PD‐123319 (3mg/kg/day) or vehicle via osmotic minipumps for 4 weeks. Chronic inhibition of the AT2R increases vascular stiffness in 12 month old females (p<0.05), but not 12 month old males or 18 month old males and females, suggesting that the AT2R contributes to the delay in aging‐associated vascular stiffness in female mice. Next, we measured AT1R‐mediated vasoconstriction and AT2R‐mediated vasodilation in second and third order mesenteric resistance vessels from 3,12, and 18 month old male and female mice. AT1R‐mediated vasoconstriction increases with age in both sexes, however, this increase occurs at 12 months in the males compared to 18 months in the females (p<0.05). Additionally, 18 month old female mice have enhanced AT1R‐mediated vasoconstriction compared to 18 month old males (p<0.05). AT2R‐mediated dilation was measured in response to sequential doses of AT2R agonist Compound‐21. For these studies, vessels were pretreated with AT1R blocker Losartan, and then preconstricted with phenylephrine. Our results show that AT2R‐mediated dilation is enhanced in 3 month females vs. 3 month males (p<0.05) and that this response is reduced with age in females (p<0.05), not males. Together, the resistance vessel studies suggest that aging‐associated alterations in angiotensin II receptor function are sexually dimorphic and may contribute to the differential manifestations of cardiovascular dysfunction observed in aging men and women.

Conclusion

These data indicate sex differences in the time course of the development of aging‐associated vascular stiffness and enhanced vasoconstriction with aging in addition to sex‐specific alterations in vascular angiotensin II receptor function with aging. Specifically, these data suggest that reductions in AT2R function contribute specifically to female vascular aging only and that AT2R restoration and/or activation may represent a novel sex‐specific therapeutic strategy in the treatment of CVD in the aging female population.

Support or Funding Information

1K12 HD092535‐01