Cerebrovascular effects of oestrogen: multiplicity of action.

1. Cerebral vessels express oestrogen receptors (ER) in both the smooth muscle and endothelial cell layers of cerebral blood vessels. Levels of ERalpha are higher in female rats chronically exposed to oestrogen, either endogenous or exogenous. 2. Chronic exposure to oestrogen, either endogenous (normally cycling females) or exogenous (ovariectomized with oestrogen replacement), results in cerebral arteries that are more dilated than arteries from ovariectomized counterparts when studied in vitro. This effect is primarily mediated by an increase in the production of vasodilator factors, including nitric oxide (NO) and prostacylin. In contrast, oestrogen appears to suppress the production of endothelial-derived hyperpolarizing factor. Oestrogen treatment increases cerebrovascular levels of endothelial nitric oxide synthase (eNOS), cyclo-oxygenase (COX)-1 and prostacyclin synthase. In addition, via activation of the phosphatidylinositol 3-kinase/Akt pathway, both acute and chronic oestrogen exposure increases eNOS phosphorylation, increasing NO production. 3. Oestrogen receptors have also been localized to cerebrovascular mitochondria and exposure to oestrogen increases the efficiency of energy production while simultaneously reducing mitochondrial production of reactive oxygen species. Oestrogen increases the production of mitochondrial proteins encoded by both mitochondrial and nuclear DNA, including cytochrome c, subunits I and IV of complex IV and Mn-superoxide dismutase. Oestrogen treatment increases the activity of citrate synthase and complex IV and decreases mitochondrial production of H(2)O(2). 4. Oestrogen also has potent anti-inflammatory effects in the cerebral circulation that may have important implications for the incidence and severity of cerebrovascular disease. Administration of lipopolysaccharide or interleukin-1beta to ovariectomized female rats induces cerebrovascular COX-2 and inducible nitric oxide synthase (iNOS) protein expression and increases prostaglandin E(2) expression. Levels of COX-2 and iNOS expression vary with the stage of the oestrous cycle, and the cerebrovascular inflammatory response is suppressed in ovariectomized animals treated with oestrogen. Interleukin-1beta induction of COX-2 protein is prevented by treatment with a nuclear factor (NF)-kappaB inhibitor, and oestrogen treatment reduces cerebrovascular NF-kappaB activity. 5. Cerebrovascular dysfunction and pathology contribute to the pathogenesis of stroke, brain trauma, oedema and dementias, such as Alzheimer's disease. A better understanding of the action of oestrogen on cerebrovascular function holds promise for the development of new therapeutic entities that could be useful in preventing or treating a wide variety of cerebrovascular diseases.