Role of aromatase in sex-specific cerebrovascular endothelial function in mice

Abstract

Stroke risk and outcome are strongly modified by estrogen. In addition to ovaries, estrogen is produced locally in peripheral tissue by the enzyme aromatase, and extragonadal synthesis becomes the major source of estrogen after menopause. Aromatase gene deletion in female mice exacerbates ischemic brain damage after stroke. However, it is not clear which cell type is responsible for this effect, since aromatase is expressed in multiple cell types, including cerebrovascular endothelium. We tested the hypothesis that cerebrovascular aromatase contributes to sex differences in cerebrovascular endothelial function. Cerebrocortical microvascular responses to the endothelium-dependent vasodilator ACh were compared between male and female wild-type (WT) and aromatase knockout (ArKO) mice by measuring laser-Doppler perfusion in vivo through a closed cranial window. Additional studies were performed in WT mice treated with the aromatase inhibitor fadrozole or vehicle. WT female mice had significantly greater responses to ACh compared with WT males (P < 0.001), which was associated with higher aromatase expression in female compared with male cerebral vessels (P < 0.05). ACh responses were significantly lower in ArKO compared with WT females (P < 0.05) and in WT females treated with fadrozole versus vehicle (P < 0.001). Conversely, ACh responses were significantly higher in ArKO versus WT males (P < 0.05). Levels of phosphorylated endothelial nitric oxide synthase (eNOS) were lower in ArKO versus WT female brains, but were not altered by aromatase deletion in males. We conclude that cerebrovascular endothelial aromatase plays an important and sexually dimorphic role in cerebrovascular function and that aromatase inhibitors in clinical use may have cardiovascular consequences in both males and females.