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 α 1C subunit (Cav α) of the Cav1.2 channel by 35%; this response did not depend on an intact endothelium. The 17βE‐induced loss of Cav α protein in coronary arteries was prevented by the estrogen ER α/ER β antagonist, ICI 182,780, whereas the GPER antagonist, G15, did not prevent it. There was no effect of 1 nmol/L 17βE on Cav α 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.

Our lab has previously demonstrated that a physiological concentration (1 nM) of estrogen (E2) can downregulate voltage‐gated, L‐type Ca2+ (VGCC) channels in coronary arteries. The distal ends of coronary arteries obtained from hearts of female pigs were sectioned into longitudinal strips and incubated for 24 hrs in 1 nM E2, EtOH, an estrogen receptor (ER) α/β antagonist (ICI 182,780), and a G protein‐coupled ER antagonist (GPER; G15). The arterial strips were homogenized for Western blot analysis using an antibody reactive to the VGCC alpha1C subunit and protein kinase Gα. Our preliminary results suggest that the E2 induced VGCC downregulation is mediated through ER α/β, and not GPER. Furthermore, ER activation by E2 in endothelium intact arteries have an increase in PKG expression (known to inhibit VGCCs), decrease in VGCC expression, and less coronary arterial reactivity. Overall, our results suggest that the classical ERs can be therapeutically targeted in women to reduce the density of VGCCs. Support: NCRR of the NIH, Grant #P20 RR‐16460 and the Arkansas SURF program.