Estrogen has long been thought to have a protective effect within the cardiovascular system. This notion is supported by the fact that females often remain protected from cardiovascular disease (CVD) compared to age-matched males, but risk for CVD increases in post-menopausal females, a state associated with decreased plasma estrogen. However, studies now suggest that prolonged exposure to estrogen, such as through continuous use of estrogen-containing contraceptives or hormone therapies, also increases CVD risk. We have recently shown that prolonged exposure to 17β-estradiol (E2) promotes microvascular endothelial dysfunction in isolated human arterioles. Because microvascular dysfunction precedes the onset of CVD, elucidating the mechanisms by which chronic estrogen exposure impairs endothelial function will address a critical knowledge gap in understanding how long-term estrogen use contributes to increased CVD risk. Cellular senescence, a state of increased oxidative stress and irreversible cell-cycle arrest, can result from continuous exposure to stress (stress-induced premature senescence). We therefore hypothesized that prolonged exposure to E2 would stimulate stress-induced premature senescence as evidenced by an increase in endothelial expression of senescence markers in isolated human microvessels. Microvessels (100-250µM in diameter) were collected from surgically discarded adipose tissue of healthy adult females and treated with 17β-estradiol (100nM, 16-20 hours) or vehicle. Vessels were then fixed in 4% paraformaldehyde and dissected en face to expose the endothelium, prior to measuring senescent markers p16INK4a (p16) and tumor protein p53 (p53) using immunofluorescence. Expression of p16 was significantly increased in vessels treated with 100nM E2 compared to vehicle control (mean ± SEM, vehicle vs. 100nM E2, 48.4±11.1 vs. 65.7±16.4, n=7, p=0.033, paired t-test). An increased trend in p53 expression was observed in microvessels exposed to estrogen. (mean ± SEM, vehicle vs. 100nM E2, 95.3±10.09 vs. 109.1±17.52, n=4, p=0.2, paired t-test). These data suggest that chronic estrogen promotes premature endothelial cell aging, providing a potential mechanism for microvascular dysfunction observed in human microvessels following long-term estrogen exposure. 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.
Limpert et al. (Fri,) studied this question.