title: Exogenous 17-β estradiol administration blunts progression of established angiotensin II-induced abdominal aortic aneurysms in female ovariectomized mice.
abstract: BACKGROUND
  Abdominal aortic aneurysms (AAAs) occur predominately in males. However, AAAs in females have rapid growth rates and rupture at smaller sizes. Mechanisms contributing to AAA progression in females are undefined. We defined effects of ovariectomy, with and without 17-β estradiol (E2), on progression of established angiotensin II (AngII)-induced AAAs in female mice.
  
  
  METHODS
  We used neonatal testosterone exposures at 1 day of age to promote susceptibility to AngII-induced AAAs in adult female Ldlr (-/-) mice. Females were infused with AngII for 28 days to induce AAAs, and then stratified into groups that were sham, ovariectomized (Ovx, vehicle), or Ovx with E2 administration for 2 months of continued AngII infusions. Aortic lumen diameters were quantified by ultrasound and analyzed by linear mixed model, and maximal AAA diameters were analyzed by one-way ANOVA. Atherosclerosis was quantified en face in the aortic arch. AAA tissue sections were analyzed for cellular composition. We quantified effects of E2 on abdominal aortic smooth muscle cell (SMC) growth, α-actin and transforming growth factor-beta (TGF-β) production, and wound healing.
  
  
  RESULTS
  Serum E2 concentrations were increased significantly by E2. Aortic lumen diameters increased over time in sham-operated and Ovx (vehicle) females, but not in Ovx females administered E2. At day 70, E2 administration decreased significantly aortic lumen diameters compared to Ovx vehicle and sham-operated females. Compared to Ovx females (vehicle), maximal AAA diameters were reduced significantly by E2. AAA tissue sections from Ovx females administered E2 exhibited significant increases in α-actin and decreases in neutrophils compared to Ovx females administered vehicle. In abdominal aortic SMCs, E2 resulted in a concentration-dependent increase in α-actin, elevated TGF-β, and more rapid wound healing. E2 administration to Ovx females also significantly reduced atherosclerotic lesions compared to sham-operated females. This effect was accompanied by significant reductions in serum cholesterol concentrations.
  
  
  CONCLUSIONS
  E2 administration to Ovx females abolished progressive growth and decreased severity of AngII-induced AAAs. These effects were accompanied by increased SMC α-actin, elevated TGF-β, and reduced neutrophils. Similarly, E2 administration reduced AngII-induced atherosclerosis. These results suggest that loss of E2 in post-menopausal females may contribute to progressive growth of AAAs.
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Room 521b, Charles T. Wethington Bldg, Lexington, KY 40536-0200 USA.
authors.forename: Sean E
authors.initials: SE
authors.lastname: Thatcher
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Room 521b, Charles T. Wethington Bldg, Lexington, KY 40536-0200 USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Room 521b, Charles T. Wethington Bldg, Lexington, KY 40536-0200 USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Woody
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Room 521b, Charles T. Wethington Bldg, Lexington, KY 40536-0200 USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Room 521b, Charles T. Wethington Bldg, Lexington, KY 40536-0200 USA.
authors.forename: Yasir
authors.initials: Y
authors.lastname: Alsiraj
authors.affiliation: Department of Statistics, University of Kentucky, Lexington, KY 40536 USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Charnigo
authors.affiliation: Saha Cardiovascular Center, University of Kentucky, Lexington, KY 40536 USA ; Department of Physiology, University of Kentucky, Lexington, KY 40536 USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Daugherty
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Room 521b, Charles T. Wethington Bldg, Lexington, KY 40536-0200 USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cassis
keywords: Abdominal aortic aneurysms; Angiotensin; Atherosclerosis; Estrogen; Transforming growth factor-beta