Abstract TP431: Role of Aromatase in Cerebrovascular Endothelial Function in Female Mice

Women are at lower risk for stroke than age-matched men even after menopause when ovarian estrogen is lost and the major source of estrogen becomes local (extra-gonadal) synthesis by the enzyme aromatase. Aromatase gene deletion in ovariectomized female mice exacerbates ischemic brain damage after stroke. It is not clear however which cell type is responsible for this effect, since aromatase is expressed in multiple cell types in brain, including cerebrovascular endothelium. Therefore, we tested the hypothesis that endothelial aromatase plays an important role in endothelium-dependent cerebrovascular function in females, which in part contributes to the sex difference in endothelial function in the cerebral microcirculation. Cerebrocortical microvascular responses to the endothelium-dependent vasodilator acetylcholine (ACh; 1-100 μM) were compared between male and female wild-type (WT) and aromatase knockout (ArKO) mice using an in-vivo closed cranial window preparation combined with laser Doppler perfusion monitoring. WT female mice had significantly greater response to ACh at doses between 10-100 μM (10 μM = 267 +/- 41%, 100 μM= 273 +/- 51%) compared to both WT male (10 μM = 144 +/- 19%, 100 μM= 156 +/- 19%) and ArKO female mice (10 μM= 158 +/- 21%, 100μM = 165 +/- 22%) (mean +/- SEM, *p<0.01, ANOVA). We conclude that aromatase plays an important role in endothelium-dependent vascular responses in female cerebral vessels, which may contribute to the observed sex differences in cerebrovascular function and response to ischemic injury.

2,3,7,8-TCDD exposure, endothelial dysfunction and impaired microvascular reactivity

Vascular function was examined in subjects with long-term high level of serum 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) during their follow-up visits. Their earlier mean peak TCDD level at the time of exposure in 1965—1968 was estimated in the range of 3300—74 000 pg/g lipids. Ten former pesticide production workers heavily exposed to TCDD (age 57 ± 2 years, TCDD about 170 pg/g lipids) were examined in 2001. Extended group of 15 TCDD-exposed men (age 59 ± 3 years, TCDD about 130 pg/g lipids) underwent the same examination in 2004. Findings were compared with a control group of 14 healthy men (age 54 ± 2 years). Skin microvascular reactivity (MVR) was measured by laser Doppler perfusion monitoring in the forearm during post-occlusive reactive hyperemia (PORH) and thermal hyperemia (TH). Several parameters of MVR in men exposed to TCDD were significantly impaired, compared with the control group and further progression of the impairment of MVR has been observed between years 2001 and 2004. Serum concentration of E-selectin and inhibitor of tissue plasminogen activator 1 (PAI-1) was significantly higher in exposed subjects (56.0 ± 18.4 ng/mL versus 40.0 ± 12.0 ng/mL, P = 0.022 and 90.9 ± 33.3 ng/mL versus 45.0 ± 18.0, P = 0.002, respectively). In addition, PORH in the forearm was significantly negatively associated with SOD activity (r = —0.77, P = 0.009) as well as the velocity of perfusion increase during TH (r = —0.68, P = 0.03) and TH% (r = —0.78, P = 0.008). Our data document the presence of endothelial dysfunction in TCDD-exposed men. Human & Experimental Toxicology (2007) 26, 705— 713