Aging and menopause additively contribute to female arterial stiffening

Introduction: Aging associated arterial stiffening is a major contributing component to cardiovascular deterioration, with noted sexual dimorphisms. In males, arterial stiffening and resultant increase in cardiovascular disease (CVD) risk is initiated by middle age. However, while women are relatively protected from CVD risk in their reproductive years, they suffer a significant risk acceleration after menopause. Remodeling of the vascular extracellular matrix (ECM) and vascular smooth muscle cell (VSMC) derangements jointly drive arterial stiffening. However, specific molecular and cellular mechanisms that drive post-menopausal vascular dysfunction and stiffening in the early and late phase following menopause remain unknown. The goal of this study is to decouple the effect of menopause on arterial stiffening from aging itself. Methods: Following OVX/sham surgery at ~2 months old (mo) on C57Bl/6J female mice, in vivo longitudinal measures (body weight, blood pressure (BP), and pulse wave velocity (PWV)) were recorded from 3 to 18 mo. End point measures were conducted at 4 mo representing young mice (sham) and early post-menopause stage (OVX), and at 18 mo representing old mice (sham) and late post-menopause stage (OVX). Aorta was extracted and cut into segments used for tensile testing to study mechanical properties, wire myography for vasoreactivity, fixed for histology analysis, or flash frozen for western blotting. Results: Longitudinal PWV revealed a large magnitude increase immediately following OVX, suggesting that menopause alone is sufficient to cause arterial stiffening; as well as a notable acceleration in PWV rate at 15 mo, suggesting that there is an aging dependent acceleration. The additive effect of aging and menopause was further apparent from a marked acceleration in the PWV at the perimenopause stage (12 mo). Despite the higher PWV, systolic BP was similar in OVX and sham females at all ages. BP increased with age in both groups, reaching higher values only at 18 mo, suggesting that aging rather than menopause is the critical factor in systolic hypertension in females. Both OVX and sham mice gained weight with age, but OVX led to a rapid weight gain immediately following surgery, and OVX females remained heavier than sham at all ages. Tensile testing showed that both cells and ECM collaboratively define overall bulk stiffness in the aged female aorta, while at the early phase following OVX the cellular components are the chief determinant of elevated arterial stiffening. Wire myography showed VSMC hypercontractility following OVX, which was later superseded by aging effect leading to attenuated contractility. Endothelial dysfunction occurred in young OVX, with no further aging effect. OVX resulted in amplified collagen synthesis only, while aging led to increased collagen incorporation and ECM stiffening, with larger wall thickness and intralamellar distance. Aging and OVX both resulted in increased matrix remodeling enzymes and collagens I and IV in the female aorta. Conclusion: Precipitated menopause causes an acute increase in arterial stiffness that is exacerbated by aging. Aging is the main cause of systolic hypertension, independent of precipitated menopause. Weight gain with aging is worsened with OVX and natural menopause. Aortic stiffening following precipitated menopause is due to VSMC dysfunction in early phase and ECM remodeling in later phase. Aging and OVX lead to smooth muscle and endothelial dysfunction. Aging is the primary mediator of macroscopic structural changes in the female vasculature. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.