Integrative Physiology Transient Exposure of Neonatal Female Mice to Testosterone Abrogates the Sexual Dimorphism of Abdominal Aortic Aneurysms

Objective: To define the role of developmental testosterone exposures in sexual dimorphism of AAAs, we determined if exposure of neonatal female mice to testosterone confers adult susceptibility to AngII-induced AAAs. Methods and Results: One-day– old female hypercholesterolemic mice were administered a single dose of either vehicle or testosterone. Neonatal testosterone administration increased abdominal aortic AT1aR mRNA abundance and promoted a striking increase in AngII-induced AAAs in adult females exhibiting low serum testosterone concentrations. AngII-induced atherosclerosis and ascending aortic aneurysms were also increased by testosterone administration to neonatal females. In contrast, neonatal testosterone administration in males had no effect on AngII-induced vascular pathologies. Deficiency of AT1aR in smooth muscle cells reduced effects of neonatal testosterone to promote AAAs in adult females but did not alter atherosclerosis or ascending aortic aneurysms. Testosterone increased AT1aR mRNA abundance and hydrogen peroxide generation in cultured abdominal aortic SMCs. Increased AT1aR mRNA abundance was maintained during progressive passaging of female smooth muscle cells. A bdominal aortic aneurysms (AAA) are permanent dila-tions of the abdominal aorta with an 85% chance of death after rupture. 1–3 Recent estimates of AAA prevalence are 1.1 million people in the US aged 50 to 84. 4 As the population lives longer, it is anticipated that AAA prevalence will increase, which is of concern because there is no proven medical therapy to change aneurysm growth or rupture. A variety of risk factors influence AAA formation and progression including age, 5,6 smoking, 7–9 obesity, 10,11 and gender. 12,13 Several studies have demonstrated that male sex is a prominent risk factor for human AAAs, 6,14,15 with recent results from the Troms´ø study estimating that males are 2.66 times as likely as females to develop AAAs. 15 Despite a strong influence of male sex on AAA formation, mechanisms contributing to increased AAA formation in males are unclear. Angiotensin II (AngII) infusion into hypercholesterolemic mice increased atherosclerosis and induced formation of aneurysms in both the ascending and suprarenal aortas of male mice. 16 –18 Notably, the renin-angiotensin system has been clinically implicated in the etiology of atherosclero-sis, ascending aortic aneurysms, and AAAs. 19,20 In mice, these AngII-induced vascular pathologies are mediated through angiotensin type 1a receptors (AT1aR). 21–23 Although each of these vascular pathologies are induced by infusion of AngII, only AAAs exhibit marked sexual dimorphism with a higher prevalence (4-fold) in male compared to female mice. 16,17,24,25 Testosterone was determined to be a primary mediator …