Influence of Estradiol and Estrogen Receptors on NOS3 Expression and Nitric Oxide Release: Implications for Intracranial Aneurysm Formation and Rupture

Abstract The prevalence of intracranial aneurysms (IAs) and aneurysmal subarachnoid hemorrhage (aSAH) due to IA rupture, is higher in postmenopausal compared with premenopausal women and men in the same age group. This is presumably due to reduced levels of the vascular protective hormone, estradiol. Experimental studies have revealed direct effects of estradiol on the vascular endothelium. Our aim was to determine the influence of estradiol and estrogen receptors on cerebral vasculature and the role of estrogen-mediated nitric oxide (NO) pathway in the formation and rupture of IAs. We measured circulatory estradiol and NO levels and the relative expression of genes involved in estrogen-mediated NO synthesis in 349 aSAH patients and 360 age- and gender-matched controls. We observed significantly reduced serum estradiol and NO levels in aSAH patients compared with controls. The expression of endothelial NO synthase gene (NOS3), estrogen receptor genes (ESR1, ESR2), and the kinases (SRC, AKT1, PIK3R1) involved in NO synthesis was significantly reduced in IA tissues compared with controls. Serum estradiol positively and significantly correlated with NO levels. Our results indicate that the activity of endothelial NO synthase and the bioavailability of NO may be regulated by estradiol and estrogen receptors to maintain cerebral vascular tone.