Poster Presentation: Hannah Wilker

ABSTRACT

It’s Time to Ovary-Act: Characterizing the Impacts of Reproductive Senescence and Aging on Aortic Function and Mechanics

Authors: Hannah Wilker1, Amanda Dias1, Ana Vargas1, Simone Sabnis1, Grace Kelly1, Rouzbeh Amini1,2, Chiara Bellini1

1Department of Bioengineering, Northeastern University
2Department of Mechanical & Industrial Engineering, Northeastern University

Objective: To determine the vascular impacts of ovarian senescence independently and coupled with aging, in pursuit of a more translationally relevant murine model for age-related pathology.

Humans are one of six mammalian species—and the only non-cetacean—to survive past reproductive age, with human women spending >30% of their lifespan after menopause. The exhaustion of the ovarian reserve halts menstruation and dramatically reduces the production of estrogen and progesterone, impacting everything from the musculoskeletal system to the vasculature. Cardiovascular disease (CVD) in particular remains the global leading cause of morbidity and mortality, as the elderly population continues to grow. CVD incidence is significantly higher in males then females through middle age, but during the menopausal transition the cardioprotective effects of estrogen decline, and post-menopause CVD risk factors like hypertension develop faster in females than age-matched males. Yet, despite a clear mechanistic difference, preclinical CVD research in animal models remains overwhelmingly biased, with over 70% of studies solely including male mice. Furthermore, less than 1% of CVD preclinical studies utilize a human-like menopausal phenotype.

To induce ovarian insufficiency, we utilized 4-vinylcyclohexene diepoxide (VCD), a selectively ovotoxic molecule which leaves ovaries intact while targeting individual follicles, decreasing and eventually ceasing endocrine function.

Vasoactive testing showed two components of menopausal vascular phenotype: increased contractility (2.2x) and impaired vasodilation (reduced by 33%), suggesting vessels are overly primed for contraction and cannot effectively dilate to relieve high pressure. Passive testing in VCD mice showed an increase in the loading stress of the aortic wall, indicating that cells cannot maintain their preferred homeostatic value, and circumferential stiffening normally associated with aging. Our results show that ovarian senescence independent of aging impacts vascular function and stiffening and including it is key to translational relevance. Currently, we are applying this model to aged mice to emulate human menopause.