Ovarian steroid protection against coronary artery hyperreactivity in rhesus monkeys

Our hypothesis was that estrogen and progesterone modulate coronary artery reactivity in rhesus monkeys. Adult ovariectomized (ovx) monkeys were treated for 1, 2, or 4 wk with physiological concentrations of 17β-estradiol (E₂), natural progesterone (P), and/or therapeutic levels of medroxyprogesterone acetate (MPA). Steroid concentrations in venous blood, coronary artery estrogen receptor (ER) and progesterone receptor (PRI localization, and isolated vascular muscle cell (VMC) Ca²⁺ and protein kinase C responses to serotonin and U46619 (a thromboxane A₂ mimetic) were measured. Ovx monkey VMC responses were hyperreactive, showing prolonged increases in intracellular Ca²⁺ and protein kinase C that correlated with exaggerated in vivo coronary artery vasoconstrictor responses. The hyperreactive Ca²⁺ responses were abolished by in vivo treatment with E₂ and/or P. However, VMC from ovx monkeys treated with the combination of E₂ and MPA or E₂, P, and MPA remained hyperreactive to vasoconstrictor stimuli, suggesting that MPA negated the protective effects of E₂. ER were detected primarily in interstitial and endothelial cells and a minor fraction of the VMC. PR were localized to coronary artery VMC and interstitial cell nuclei. In vivo treatment of ovx monkeys with E₂ tended to up-regulate PR in VMC, but MPA appeared to down-regulate PR expression. These results suggest that E₂ and P replacement decreases coronary artery reactivity through direct interactions with ER and PR in coronary artery VMC.