Activation of inflammatory pathways underlies cerebrovascular disease pathology. There is a well-described gender difference in stroke incidence between men and women. Also, testosterone and male gender are associated with increased stroke risk. Thus, we explored the impact of testosterone and estrogen on cerebrovascular inflammation using both in vivo and in vitro models of inflammation. We hypothesized that testosterone will augment and estrogen will suppress the expression of two vascular markers of cellular inflammation: cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Using four groups of male rats (intact, orchiectomized [ORX], estrogen-treated [ORXE], and testosterone-treated [ORXT]), we determined the effects of gonadal steroids on cerebrovascular inflammation after i.p. lipopolysaccharide (LPS) injections. Using Western analysis, the induction of inflammatory markers was decreased in blood vessels from estrogen-treated rats compared to intact or ORX males. In contrast, in cerebral vessels from testosterone-treated rats, there was significant augmentation in LPS-induced COX-2 and iNOS protein levels. Confocal microscopy was used for cellular localization of COX-2 and iNOS. ORXT rats showed increased COX-2 and iNOS immunoreactivity in endothelial and smooth muscle cells after LPS treatment. In vitro incubations with LPS of isolated pial vessels from the same animal groups demonstrated greater COX-2 induction in ORXT rats compared to ORX and ORXE. Increases in PGE2 production, a principal prostaglandin end-product of COX-2 enzymatic activity, were also greater in vessels from ORXT rats. In conclusion, testosterone and estrogen differentially contribute to cerebrovascular inflammation. Thus, this may contribute to differences in stroke morbidity and mortality between men and women. Presently, we are exploring mechanisms by which the gonadal hormones influence the proinflammatory signaling nuclear factor kappa-B (NFkB) pathway.
Supported by NIH grant HL-50775.
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