Estrogen and the Vascular Endothelium: The Unanswered Questions

Abstract

Pre-menopausal women have a lower incidence of cardiovascular disease (CVD) compared to their age-matched male counterparts however this discrepancy is abolished following the transition to menopause or during low estrogen states. This, combined with a large amount of basic and preclinical data indicating that estrogen is vasculoprotective, supports the concept that hormone therapy could improve cardiovascular health. However, clinical outcomes in individuals undergoing estrogen treatment have been highly variable, challenging the current paradigm regarding the role of estrogen in the fight against heart disease. Increased risk for CVD correlates with long-term oral contraceptive use, hormone replacement therapy in older, post-menopausal cis-females, and gender affirmation treatment for trans-females. Vascular endothelial dysfunction serves as a nidus for the development of many cardiovascular diseases and is highly predictive of future CVD risk. Despite preclinical studies indicating that estrogen promotes a quiescent, functional endothelium, it still remains unclear why these observations do not translate to improved CVD outcomes. The goal of this review is to explore our current understanding of the effect of estrogen on the vasculature, with a focus on endothelial health. Following a discussion regarding the influence of estrogen on large and small artery function, critical knowledge gaps are identified. Finally, novel mechanisms and hypotheses are presented that may explain the lack of cardiovascular benefit in unique patient populations.

Acute brain injury and nanomedicine: sex as a biological variable

“…Expression of sex steroid hormone receptors are established in cerebral microvasculature. Estradiol binding to its receptor on endothelial cells has previously been implicated in the maintenance of the vascular system (Cho et al, 1999;Lösel and Wehling, 2003;SenthilKumar et al, 2023). For example, in vitro studies have revealed estradiol binding to endothelial cell receptors activates endothelial nitric oxide synthase, which leads to elevated nitric oxide levels and changes in paracellular permeability (Cho et al, 1999).…”

“…Notably, they found testosterone supplementation after 5 weeks restores cerebrovascular integrity and results in no significant differences in inflammatory state between castrated and intact males. Furthermore, multiple lines of evidence support sex differences in cardiovascular health and sex-dependent risk of cardiovascular disease (CVD), which can be attributed to steroid hormone profiles (SenthilKumar et al, 2023). For example, prior to menopause, females exhibit a lower risk for developing CVD compared to males.…”