17β-Estradiol promotes sex-specific dysfunction in isolated human arterioles.

Despite data showing that estrogen is vasculoprotective in large conduit arteries, hormone therapy (HT) during menopause has not proven to mitigate cardiovascular disease (CVD) risk. Estrogen exposure through prolonged oral contraceptive use and gender-affirming therapy can also increase cis- and trans-females' risk for future CVD, respectively. The microvasculature is a unique vascular bed that when dysfunctional can independently predict future adverse cardiac events; however, studies on the influence of estrogen on human microvessels are limited. Here, we show that isolated human arterioles from females across the life span maintain nitric oxide (NO)-mediated dilation to flow, whereas chronic (16-20 h) exposure to exogenous (100 nM) 17β-estradiol promotes microvascular endothelial dysfunction in vessels from adult females of <40 and ≥40 yr of age. The damaging effect of estrogen was more dramatic in arterioles from biological males, as they exhibited both endothelial and smooth muscle dysfunction. Furthermore, females of <40 yr have greater endothelial expression of estrogen receptor-β (ER-β) and G protein-coupled estrogen receptor (GPER) compared with females of ≥40 yr and males. Estrogen receptor-α (ER-α), the prominent receptor associated with protective effects of estrogen, was identified within the adventitia as opposed to the endothelium across all groups. To our knowledge, this is the first study to report the detrimental effects of estrogen on the human microvasculature and highlights differences in estrogen receptor expression. NEW & NOTEWORTHY Microvascular dysfunction is an independent predictor of adverse cardiac events; however, the effect of estrogen on the human microcirculation represents a critical knowledge gap. To our knowledge, this is the first study to report sex-specific detrimental effects of chronic estrogen on human microvascular reactivity. These findings may offer insight into the increased CVD risk associated with estrogen use in both cis- and trans-females.