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

John P. Konhilas, Jessica N. Sanchez, Jessica A. Regan, Eleni Constantopoulos, Marissa Lopez-Pier, Danielle K. Cannon, Rinku Skaria, Laurel A. McKee, Hao Chen, Yulia Lipovka, Dennis Pollow, Heddwen L. Brooks

Research output: Contribution to journalArticle

Abstract

Using 4-vinylcyclohexene diepoxide as a model of menopause for cardiovascular disease. Am J Physiol Heart Circ Physiol 318: H1461-H1473, 2020. First published May 8, 2020; doi:10.1152/ajpheart.00555.2019.-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 vs. 141.7 5.0 mmHg) blood pressure and normalized cardiac mass (15.9 1.0 vs. 7.7 1.5%) to a greater extent in menopausal females compared with 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 vs. 152.3 6.5 mmHg) blood pressure and normalized cardiac mass (8.3 2.1 vs. 7.5 1.4%) compared with controls. Similarly, menopausal females demonstrated a threefold 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.

Original languageEnglish (US)
Pages (from-to)H1461-H1473
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume318
Issue number6
DOIs
StatePublished - Jun 2020
Externally publishedYes

Keywords

  • 4-vinylcyclohexene diepoxide
  • angiotensin II
  • cardiac injury
  • hypertension
  • menopause

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Konhilas, J. P., Sanchez, J. N., Regan, J. A., Constantopoulos, E., Lopez-Pier, M., Cannon, D. K., Skaria, R., McKee, L. A., Chen, H., Lipovka, Y., Pollow, D., & Brooks, H. L. (2020). Using 4-vinylcyclohexene diepoxide as a model of menopause for cardiovascular disease. American Journal of Physiology - Heart and Circulatory Physiology, 318(6), H1461-H1473. https://doi.org/10.1152/ajpheart.00555.2019