Abstract Body: The strongest risk factor for developing cardiovascular disease (CVD) is aging, but as women and men age, their risk of CVD development is dimorphic. For women, the incidence of CVD sharply rises following menopause, but the underlying mechanism of this dimorphism remains unknown. Estrogen levels decline with age, and recent evidence suggests that unliganded estrogen receptor negatively impacts vascular function. Since microvascular dysfunction initiates the development of CVD, we hypothesized that the presence of smooth muscle cell-estrogen receptor alpha (SMC-ERα) is detrimental to microvascular function with aging.

We created novel SMC-specific ERα knockout (ERα^-/-) and intact (ERα^+/+) female (n=7-10) and male (n=6-8) mice. Second-order mesenteric arteries from 18-month-old mice were used to test endothelium-dependent dilation (EDD) and vasoconstriction using wire myography. EDD was assessed via acetylcholine (ACh) dose-response curves. The contributions of nitric oxide and endothelium-derived hyperpolarizing factors (EDHF) were quantified by inhibiting nitric oxide synthase (NOS) and calcium-activated potassium channels, respectively, in the presence of ACh. Vasoconstriction in response to phenylephrine and angiotensin II was also measured.

SMC-ERα deletion improved EDD in aged female, but not male, mice (female: p<0.05, male: p=0.96). We then assessed the contributions of NOS and EDHF to EDD. For aged female ERα^-/- mice, there was a significant increase in the contribution of NOS (p<0.01) and EDHF (p<0.05) compared to ERα^+/+ mice, but no change in the makeup of EDD in the aged male mice (NOS: p=0.57, EDHF: p=0.13). Vasoconstriction studies revealed no differences in the dose-response relationship to phenylephrine (female: p=0.13, male: p=67). However, in response to a single dose of angiotensin II (1x10^-7), there was a significant reduction in maximum constriction in female ERα^-/- mice (max force: ERα^+/+=4.8±0.4, ERα^-/-=3.9±0.2 mN, p<0.05), but no change in the male response (ERα^+/+=3.2±0.2, ERα^-/-=3.8±0.2 mN, p=0.30).

These data suggest that the presence of SMC-ERα plays a critical role in the development of microvascular dysfunction in aging female, but not male, mice. This is supported by the observed endothelial dysfunction, characterized by reductions in nitric oxide and EDHF, in female ERα^-/- mice. Future studies are warranted to determine the precise mechanism by which SMC-ERα contributes to female aging-associated microvascular dysfunction.