LAUSR

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 lifespan maintain nitric oxide (NO) mediated dilation to flow whereas chronic (16-20hrs) exposure to exogenous (100 nM) 17β-estradiol promotes microvascular endothelial dysfunction in vessels from adult females <40 yrs and ≥40 yrs of age. The damaging effect of estrogen was more dramatic in arterioles from biological males, as they exhibited both endothelial and smooth muscle dysfunction. Further, females <40yrs have greater endothelial expression of estrogen receptor beta (ER-β) and G-protein coupled estrogen receptor (GPER) compared to females ≥40 yrs and males. Estrogen receptor alpha (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 detrimental effects of estrogen on the human microvasculature and highlights differences in estrogen receptor expression.