Estrogen regulation of prostanoid pathways in the cerebral circulation

Estrogen protects against ischemic brain injury in experimental models of stroke. Regulators of cerebral circulatory function may be important targets of estrogen. This dissertation examined the effects of chronic in vivo 17β-estradiol treatment on cerebrovascular prostaglandin synthesis and function.; Chapter 2 describes the effects of 17β-estradiol on cerebrovascular prostanoid production. Prostanoid synthesis by cerebral blood vessels from 17β-estradiol-treated and non-treated ovariectomized rats was examined by ELISA. Prostanoid synthetic enzymes were examined by immunoblot analysis. Estrogen enhanced PGI₂ synthesis and increased cyclooxygenase-1 and PGI₂-synthase levels in the cerebral circulation.; Chapter 3 describes the functional consequences of estrogen-mediated prostanoid regulation. Middle cerebral arteries isolated from ovariectomized rats with or without chronic in vivo 17β-estradiol treatment were pressurized and contractile function examined. Estrogen treatment increased cerebral artery diameter in an endothelial- and cyclooxygenase-dependent manner. This correlated with increased PGI₂ production. Estrogen also suppressed an endothelial cyclooxygenase-derived constrictor that activated the thromboxane/endoperoxide receptor, but was not dependent on thromboxane-synthase. Estrogen thus appears to inhibit prostaglandin endoperoxide (i.e., PGH₂) activity.; Chapter 4 describes the effects of estrogen on cerebrovascular responses to stimulators of cAMP signaling. Cerebral vessels were isolated from ovariectomized rats with or without chronic in vivo 17β-estradiol treatment. Estrogen potentiated forskolin-stimulated cAMP synthesis without influencing adenylate cyclase mRNA expression. Cerebral artery dilation and cAMP accumulation following PGI₂ receptor stimulation were enhanced by estrogen.; Chapter 5 describes the effects of in vivo IL-1β exposure on cerebrovascular cyclooxygenase-2 expression and function in animals treated with estrogen. Estrogen-treated and non-treated ovariectomized female rats received intraperitoneal IL-1β injections and cerebral vessels were isolated for biochemical and contractile measurements. In estrogen-deficient rats, IL-1β induced endothelial cyclooxygenase-2, increased PGE ₂ production, and decreased vascular tone in cerebral arteries. The latter effect was partially reversed by selective cyclooxygenase-2 inhibition. Estrogen prevented the effects of IL-1β. IL-1β induction of COX-2 was prevented by NF-κB inhibition; estrogen reduced cerebrovascular NF-κB activity.; In conclusion, estrogen influences the biosynthesis and activity of prostanoids that regulate cerebral blood flow and thrombosis. Estrogen also suppresses cerebrovascular inflammatory prostaglandin pathways. These findings may shed light on mechanisms that contribute to gender-based differences in cerebrovascular disease.