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Estrogen Receptor Beta‐Mediated Anti‐Inflammatory Effect of Dihydrotestosterone During Cytokine‐Induced Inflammation in Human Brain Vascular Smooth Muscle Cells

Vascular inflammation plays a key role in the etiology of cardiovascular disease, particularly stoke. Previous studies have demonstrated that sex steroids modulate vascular inflammation. Our recent studies show that, in human vascular smooth muscle cells, chronic treatment with the potent androgen dihydrotestosterone (DHT) decreases expression of the pro‐inflammatory mediator cyclooxygenase‐2 (COX‐2) during cytokine‐induced inflammation or ischemia via an androgen receptor‐independent mechanism. Since DHT can be converted to 3β‐diol, an estrogen receptor (ER) β‐specific agonist, we hypothesized that DHT would decrease IL‐1β induced COX‐2 expression in primary human brain vascular smooth muscle cells via conversion to 3β‐diol and subsequent activation of ERβ. Pre‐treatment for 18h with either DHT (10nM) or its estrogenic metabolite 3β‐diol (10nM) reduced IL‐1β‐induced increases in COX‐2 expression. Pre‐treatment with the AR antagonist bicalutamide (1μM) did not block the effect of DHT. Both the non‐selective ER antagonist ICI 182,780 (1μM) and the selective ERβ‐antagonist PHTPP (1μM) inhibited the effect of DHT. In conclusion, DHT appears to be protective against cerebrovascular inflammation via conversion to 3β‐diol and subsequent activation of ERβ. Support: AHA RJG, AHA KLO, UA Sarver Heart Center Grant (KLO)