Cyclic 17β-Estradiol Exposure Maintains Human Microvascular Function

The role of estrogen on cardiovascular disease (CVD) risk has been controversial. Both estrogen deficit (menopause, ovarian failure) and prolonged estrogen (estrogen containing therapy) have been associated with a higher CVD risk. We have previously demonstrated microvascular dysfunction, an early predictor of CVD, in human resistance arterioles exposed to chronic 17β-estradiol (100nM; 20hr). This dysfunction manifested as a transition in the primary mediator of flow-induced dilation (FID) from nitric oxide (NO) to hydrogen peroxide (H 2 O 2 ) in resistance arterioles from healthy female patients. Since estrogen typically fluctuates naturally, we hypothesize that the influence of estrogen on microvascular function depends on the temporal context of exposure. To evaluate this, programmable infusion pumps were used to simulate the natural pattern of cycling estrogen. Resistance arterioles (100-150µM) dissected from surgical discard adipose specimens from healthy female patients were treated with cyclic 17β-estradiol (20-100nM; 20hr) or cyclic vehicle (100% ethanol 0.1% vol/vol; 20hr). Microvascular function was assessed by evaluating FID via pressure myography. Changes in vessel diameter was recorded via videomicroscopy in response to an increasing pressure gradient (5-100cmH 2 O) across the vessel. The primary mediator of dilation was evaluated by the addition of Nω-nitro-L-arginine methyl ester (L-NAME; 10-4mol/L), or polyethylene glycol-catalase (PEG-catalase; 500 U/mL), inhibitors of NO or H 2 O 2 -mediated FID respectively. Arterioles treated with cyclic 17β-estradiol maintained NO-mediated FID, shown by a significant reduction in FID magnitude with L-NAME versus estrogen alone (%Maximal Dilation ± SEM, Cyclic 17β-Estradiol with L-NAME vs estrogen alone, 55.2% ±5.3 vs 79.6% ± 3.6, n=6 vs n=12, respectively, p=0.0240, two-way ANOVA). FID was however maintained following PEG-catalase treatment (90.5% ± 3.0, n=5). Interestingly, arterioles treated with cyclic vehicle showed no significant reduction in FID with L-NAME or PEG-catalase, suggesting partial mediation of FID via NO and H 2 O 2 . Together, these data suggest that cyclic 17β-estradiol maintains NO-mediated FID compared to chronic estrogen exposure. Furthermore, cyclic 17β-estradiol maintains NO-mediated FID, despite cyclic vehicle eliciting potential damage to the microvasculature with partial NO and H 2 O 2 -mediated FID. These findings add insight to the time-dependent actions of estrogen and advance our understanding of its complex role in both maintaining cardiovascular health and driving cardiovascular pathology. 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.