Using 4-vinylcyclohexene diepoxide as a model of menopause for cardiovascular disease

There is a sharp rise in cardiovascular disease (CVD) risk and progression with the onset of menopause. The 4-vinylcyclohexene diepoxide (VCD) model of menopause recapitulates the natural, physiological transition through perimenopause to menopause. We hypothesized that menopausal female mice were more susceptible to CVD than pre- or perimenopausal females. Female mice were treated with VCD or vehicle for 20 consecutive days. Premenopausal, perimenopausal and menopausal mice were administered angiotensin II (Ang-II) or subjected to ischemia/reperfusion (I/R). Menopausal females were more susceptible to pathological Ang-II-induced cardiac remodeling and cardiac injury from a myocardial infarction (MI), while perimenopausal, like premenopausal females, remained protected. Specifically, Ang II significantly elevated diastolic (130.9±6.0 vs. 114.7±6.2 mmHg) and systolic (156.9±4.8 mmHg vs. 141.7±5.0 mmHg) blood pressure and normalized cardiac mass (15.9±1.0% vs. 7.7±1.5%) to greater extent in menopausal females compared to controls, whereas perimenopausal females demonstrated a similar elevation of diastolic (93.7±2.9 vs. 100.5±4.1 mmHg) and systolic (155.9±7.3 mmHg vs. 152.3±6.5 mmHg) blood pressure, normalized cardiac mass (8.3±2.1% vs. 7.5±1.4%) compared to controls. Similarly, menopausal females demonstrated a 3-fold increase in fibrosis measured by picrosirus red staining. Finally, hearts of menopausal females (41±5%) showed larger infarct sizes following I/R injury than perimenopausal (18.0±5.6%) and premenopausal (16.2±3.3%, 20.1±4.8%) groups. Using the VCD model of menopause, we provide evidence that menopausal females were more susceptible to pathological cardiac remodeling. We suggest that the VCD model of menopause may be critical to better elucidate cellular and molecular mechanisms underlying the transition to CVD susceptibility in menopausal women.