Abstract Body: Background: Arterial stiffness is an independent predictor of cardiovascular events and mortality. Clinical data shows arterial stiffness increases rapidly after menopause, but mechanisms that mediate this change are not well known. The effect of ovariectomy (ovx) in rodent models is inconsistent in the literature. We hypothesize that the loss of estradiol (E2) contributes to ovx-induced arterial stiffening in a mouse model via fibrotic mechanisms, and that restoration of E2 will prevent these changes.
Methods: Eight-week-old female C57/Bl6J mice received bilateral ovx or sham operation. Subcutaneous placebo or E2 (0.36 mg/day) pellets were implanted 2 weeks later to achieve three groups (sham+placebo, ovx+placebo, and ovx+E2). Aortic pulse wave velocity (PWV) was measured as an index of arterial stiffness. Blood pressure (BP) was measured by radiotelemetry. Aortic fibrosis was assessed by histological quantification of Masson’s trichrome staining and expressed as fold change in %fibrosis from sham. Pro-fibrotic genes were assessed in aortic tissue via quantitative PCR. Data presented are mean ± SEM.
Results: Successful ovx was confirmed by reduction in uterine weight in the ovx group compared with other groups (p<0.0001). At 6-weeks-post-surgery (N=16-18/group), PWV was increased in ovx (5.2±0.2 mm/ms) versus sham (3.4±0.1 mm/ms, p<0.0001) and ovx+E2 (3.5±0.1 mm/ms, p<0.0001) groups. In biweekly measures (N=4-5/group), PWV was greater in the ovx group at 4- and 6-weeks-post-surgery compared with sham (p<0.0001) and ovx+E2 (p<0.0001) groups, while PWV in the ovx+E2 group did not differ from sham at any time (p≥0.6). At 6-weeks post-surgery (N=5/group), there were no observed differences between groups for dark or light cycle systolic or diastolic BP, mean arterial pressure, or pulse pressure. Aortic fibrosis was increased in the ovx group (1.6-fold) compared with sham (p=0.03) and ovx+E2 (0.9-fold, p=0.02) groups (N=10-12/group). Aortic fibrosis correlated with PWV at 6-weeks-post-surgery (R²=0.25, p<0.01). Aortic mRNA expression of collagen1a1 was increased in ovx versus ovx+E2 mice (p=0.04, N=4-6/group).
Conclusion: In conclusion, the restoration of E2 prevents ovx-driven arterial stiffening in female mice via a reduction in fibrotic remodeling of the aorta. The results also support that ovx is an appropriate model to study the mechanisms of menopause-induced arterial stiffening and that anti-fibrotic therapeutics may be beneficial in aging women.