Mechanisms of cerebrovascular protection: oestrogen, inflammation and mitochondria.

Investigation of oestrogen action reveals a multitude of diverse effects. This brief review focuses on the impact of oestrogen on the vasculature, with particular emphasis on the cerebral circulation. Three major actions of oestrogen are discussed: enhancement of vasodilator capacity, suppression of vascular inflammation and increase in mitochondrial efficiency. In both humans and animals, oestrogen increases vasodilator tone, an effect dependent on a functional endothelium. Two distinct mechanisms are involved: increase in endothelial nitric oxide synthase (eNOS) mRNA and protein and phosphorylation of eNOS via the PI-3 kinase/Akt pathway. Both effects are mediated by oestrogen receptors (ER), but through two pathways, ER-mediated nuclear gene transcription and cell membrane-associated ERs respectively. Oestrogen also increases function of other endothelium-dependent vasodilators. Oestrogen suppresses vascular inflammation through an NF-κB-dependent effect. The inflammatory response has also been shown to vary significantly during the oestrous cycle of rodents. Emerging information shows that oestrogen increases mitochondrial biogenesis and decreases superoxide production. Suppression of mitochondrial superoxide production by 17β-estradiol in cerebral blood vessels is mediated by the ER-alpha receptor and not dependent on increased Mn superoxide dismutase activity. Oestrogen treatment also increases protein levels for a number of components of the electron transfer chain, as well as levels of transcription factors that regulate mitochondrial function. All of these actions of oestrogen could be important in mediating vascular protection, especially in the cerebral circulation. Furthermore, given the potential of mitochondrial DNA damage to contribute to pathophysiology and ageing, mitochondrial protective effects of oestrogen might contribute to the longer average lifespan of women.