Is Estrogen a Friend or Foe of the Human Microcirculation Throughout the Lifespan?

Abstract

Cardiovascular disease (CVD) risk increases with estrogen (E2) deficiency as well as during the transition to menopause, suggesting that estrogen is protective against CVD. On the contrary, increases in plasma E2 from contraception in cis‐females or hormone therapy (HT) in trans‐females (male‐to‐female transition) is also associated with increased CVD. Microvascular endothelial dysfunction, or the loss of nitric oxide (NO)‐mediated dilation in response to flow (flow‐induced dilation; FID), precedes large artery disease and is predictive of future cardiac events. We hypothesize that the effect of E2 on human microvascular endothelial function is hormetic with low or elevated E2 promoting dysfunction. We further posit that the effect of estrogen on the microvascular endothelium is influenced by both age and sex. Small adipose arterioles (100‐350µm) from healthy adults (0‐1 risk factors for coronary artery disease) were prepared for videomicroscopy and constricted with endothelin‐1 prior to measuring changes in internal diameters in response to flow. Historical data was analyzed to examine changes in FID over time in healthy women, and it showed that FID is maintained over time (75.4%±4.2 of maximal dilator capacity±SEM, n=26 age<40yrs; 75.39%±3.0 age>40yrs). L‐NAME significantly inhibited FID in healthy women <40yrs of age (30.6%±9.9 n=17; p<0.0005, two‐way ANOVA*) compared to control (75.4%±4.2, n=26), however this effect was abolished when incubated with E2 (100nM, 16‐20hrs) (71.2%±10.3, n=5 vs. control 84.7%±3.8, n=5). L‐NAME also decreased FID in arterioles from women 40‐60yrs of age (46.9%±9.8, n=19) compared to control (81.3%±2.6, n=37, p<0.005), however there was a greater amount of residual dilation compared to women <40yrs. E2 also resulted in a loss of NO‐mediated FID in women >40yrs as L‐NAME had no effect (82.9%±4.3, n=4 vs. control 72.6%±8.8, n=5). In biological males, FID appears to be reduced in microvessels after E2 treatment regardless of age (52.1%±5.1 n=2, age<40yrs; ‐2.7%±9.5, n=3, age>40yrs). Together these data suggest that exposure to elevated levels of E2 may induce microvascular endothelial dysfunction in adult women regardless of age and appears to be more damaging in biological males. We conclude that elevated levels of E2 are detrimental to the microvasculature and may increase CVD risk in young women taking oral contraceptives as well as older women and trans‐females undergoing HT.