Fellowship for Alsiraj: Sex Differences in Angiotensin-induced AAAs

Abdominal aortic aneurysms (AAAs) are permanent dilations of the abdominal aorta with an 85% chance of death after rupture affecting more than 1.1 million people in the US aged 50 to 84. Male sex is one of the strongest risk factors for AAAs; with estimates ranging from a 2-10 fold greater prevalence in males than females. Similar to the human disease, AAAs induced by infusion of Angiotensin II (AngII) to hypercholesterolemic mice exhibit marked sexual dimorphism, with a 4-fold higher prevalence in male compared to female mice. Previous studies in our lab demonstrated that testosterone is the primary mediator of higher AAA prevalence in adult AngII-infused male mice by promoting a region-specific increase in Angiotensin receptor type1a (AT1aR) mRNA abundance in abdominal aortas that closely parallels AAA susceptibility. Our lab also demonstrated that administration of a single dose of testosterone to neonatal females resulted in a robust increase in AAA susceptibility of adult females. This increased AAA susceptibility of adult females exposed neonatally to testosterone was associated with increased AT1aR expression in abdominal aortas. Recent studies suggest that in addition to sex hormones, sex chromosome complement can influence blood pressure responses to AngII. In addition, Turner’s Syndrome (monosomy X) is associated with aneurysm pathology in humans. Preliminary data suggest that the sex chromosome complement may influence expression levels of components of the renin-angiotensin system. The central hypothesis of this proposal is that sex chromosome effects, in addition to sex hormones, contribute to sexual dimorphism of AngII-induced AAAs. Aim 1 will define the relative contribution of sex hormones versus sex chromosomes as determinants of susceptibility to AngII-induced AAAs, while aim 2 will define the sex chromosome complement effect on the ability of neonatal testosterone to promote AngII-induced AAAs in female mice. Results from these studies may identify targets, amenable to therapy, that either protect (females) or augment (males) AAA susceptibility.