Abstract 055: Estrogen And Smooth Muscle Cell Estrogen Receptor Alpha Modulate Arterial Stiffness

Abstract

Background: Arterial stiffness increases with age and contributes to cardiovascular disease. Although sex differences in arterial stiffness are clinically observed, the underlying mechanisms are unknown. Specifically, the role of estrogen (E2) and estrogen receptor alpha (ERα) in sex-dependent differences in arterial stiffness have not been defined. We hypothesize that E2 and ERα contribute to sex differences in arterial stiffness. Methods/Results: We measured aortic pulse wave velocity, an index of arterial stiffness, at 3, 12, and 18 months old, in male and female mice. Arterial stiffness increased in males at 12 and 18m but was delayed until 18m in females (p<0.05). Circulating E2 decreased with age in females (p<0.05), suggesting a link between estrogens and arterial stiffness. In young female mice, arterial stiffness increased with ovariectomy (OVX) versus sham surgery but was restored in OVX mice plus E2 pellet (p<0.05). Aortic gene expression for the vasoprotective angiotensin II type 2 receptor (AT2R) decreased with OVX versus sham and was restored in OVX mice plus E2 pellet (p<0.05). These data suggest a link between arterial stiffness, E2, and AT2R. We therefore created novel SMC-specific ERα knockout (SMC-ERα-KO) mice to assess the role of SMC-ERα in sex differences in arterial stiffness. Differences in arterial stiffness with age persist in ERα-intact mice, but 18m SMC-ERα-KO males and females exhibited less stiffness vs. age-matched ERα-intact littermates (p<0.05). Trends persist in repeat PWV measures at 12 and 16-18m in individual males and females. Blood pressure (via telemetry) did not differ between 18m intact and KO males or females (p=0.73). In young ERα-intact females, OVX increased stiffness and decreased aortic AT2R expression, while OVX had no effect in SMC-ERα-KO females (all p<0.05), supporting a role for E2 and SMC-ERα in arterial stiffness. Conclusion: These data suggest that estrogen contributes to sex differences in arterial stiffness and that with advancing age, SMC-ERα is unliganded due to the loss of estrogen and contributes to arterial stiffness in females, potentially via alterations in vascular AT2R function. These results also suggest a detrimental role for SMC-ERα in aging-associated arterial stiffness in males.