17β-estradiol reduces Cav1.2 channel abundance and attenuates Ca2+-dependent contractions in coronary arteries

One mechanism by which the female sex may protect against elevated coronary vascular tone is inhibition of Ca2+ entry into arterial smooth muscle cells (ASMCs). In vitro findings confirm that high estrogen concentrations directly inhibit voltage-dependent Cav1.2 channels in coronary ASMCs. For this study, we hypothesized that the nonacute, in vitro exposure of coronary arteries to a low concentration of 17β-estradiol (17βE) reduces the expression of Cav1.2 channel proteins in coronary ASMCs. Segments of the right coronary artery obtained from sexually mature female pigs were mounted for isometric tension recording. As expected, our results indicate that high concentrations (≥10 μmol/L) of 17βE acutely attenuated Ca2+-dependent contractions to depolarizing KCl stimuli. Interestingly, culturing coronary arteries for 24 h in a 10,000-fold lower concentration (1 nmol/L) of 17βE also attenuated KCl-induced contractions and reduced the contractile response to the Cav1.2 agonist, FPL64176, by 50%. Western blots revealed that 1 nmol/L 17βE decreased protein expression of the pore-forming α1C subunit (Cavα) of the Cav1.2 channel by 35%; this response did not depend on an intact endothelium. The 17βE-induced loss of Cavα protein in coronary arteries was prevented by the estrogen ERα/ERβ antagonist, ICI 182,780, whereas the GPER antagonist, G15, did not prevent it. There was no effect of 1 nmol/L 17βE on Cavα transcript expression. We conclude that 17βE reduces Cav1.2 channel abundance in isolated coronary arteries by a posttranscriptional process. This unrecognized effect of estrogen may confer physiological protection against the development of abnormal Ca2+-dependent coronary vascular tone.