Sex Differences in Angiotensin-Induced Vascular Diseases

Abdominal aortic aneurysms (AAAs), affecting more than 1.1 million people in the US aged 50 to 8414 are permanent dilations of the abdominal aorta with an 85% chance of death after rupture. There are no therapeutic strategies proven to blunt AAA progression, making surgery the only available option . Thus, delineation of mechanisms contributing to AAA formation and progression is paramount to the development of effective therapies 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. Given the strong predisposition to AAA formation in males, definition of the mechanistic basis for sexual dimorphism of AAAs may delineate potential targets, amenable to therapy, that either suppress (in females) or augment (in males) AAA formation and progression Similar to the human disease, AAAs induced by infusion of angiotensin II (Angll) to hypercholesterolemic mice exhibit marked sexual dimorphism, with a 4-fold higher prevalence in male compared to female mice ts Our previous studies demonstrated that testosterone is a primary mediator of higher AAA prevalence in adult Angll-infused male mice '5 To define the mechanistic basis for testosterone promotion of AAA formation, we focused on angiotensin type 1a receptor (AT1aR) expression in the aorta, since whole body deficiency of AT1 aR totally ablated Angll-induced AAAs, and since testosterone enhances some responses of the cardiovascular system to Angll. '7 We demonstrated that testosterone promotes a region-specific increase in AT1aR mRNA abundance in abdominal aortas that closely parallels AAA susceptibility .16 To define the basis for region-specific effects of testosterone on aortic AT1 aR expression, we focused on embryonic origins of medial smooth muscle cells (SMCs), since SMC are well defined cell targets'8 of Angll in the regulation of vascular function. Smooth muscle of the abdominal aorta, the site for AAA formation, is of splanchnic mesoderm origin, and cells of this embryonic origin express androgen receptors (AR) during development This suggests that testosterone effects at mesodermal cells during development may initiate AT1 aR expression to SMCs of this embryonic origin, contributing to enhanced AT1 aR expression in abdominal compared to thoracic aortas. To test this hypothesis, we mimicked developmental exposures to testosterone in males'o.2' by exposing 1 day old neonatal females to a single dose of testosterone, and examined AAA susceptibility as adults. Remarkably, exposure of 1 day old female apolipoprotein E (ApoE) or low density lipoprotein (LDLR) deficient mice to testosterone promoted a striking region-speclflc Increase in abdominal aortic AT1aR expression, and markedly increased AAA susceptibility of adult females. Effects of testosterone during development to promote AAA susceptibility in adult females were dose-dependent. Importantly, since circulating testosterone concentrations In adult females were not influenced by neonatal testosterone exposures, these effects were long-lasting and did not require continued testosterone exposures as adults. Deficiency of AT1 aR in SMC blunted effects of neonatal testosterone to promote AAA susceptibility in adult females, but had no effect on Angll-induced atherosclerosis or ascending aortic aneurysms. While SMCs are a logical target of testosterone to promote A T1aR expression and increase AAA susceptibility, it is unclear which cell type mediates these powerful effects of testosterone. An interesting feature of these studies is the difference in responses of neonatal male and female mice to testosterone. For example, administration of the same dose of testosterone to neonatal males, superimposed on endogenous testosterone surges, had no effect on susceptibility of adult males to AAA formation. Further, males required continued testosterone exposures as adults to maintain region-specific increases in AT1aR mRNA abundance and AAA susceptibility, while females did not. Finally, exposures of neonatal females to testosterone increased Angll-induced atherosclerosis and ascending aortic aneurysms, even though these pathologies do not exhibit sex differences between adult males and females. These results demonstrate that while important, sex hormones cannot totally explain differences between males and females in vascular disease development. Recent studies demonstrated that blood pressure responses to Angll in mice are influenced by sex chromosome complemenf2 , suggesting that other responses to Angll may also be sex chromosome dependent We will use the four core genotype mouse model to dissect out the relative contlibution of sex hormones to chromosomes as mediators of AAA susceptibility, with a goal to identify genes on sex chromosomes or regulated by sex hormones as novel targets that could be exploited to develop AAA therapies. The central hypothesis of this proposal is that testosterone effects (developmental and/or adult) at pivotal cell types, in addition to sex chromosome effects, promote region-specific increases in aortic AT1aR expression and Angll-induced AAAs. Specific Aim 1. Define the cell-specific role of AR in developmental and/or adult effects of testosterone on abdominal aortic AT1aR expression and Angll-induced AAAs .. Specific Aim 2. Define the relative contribution of sex hormones versus sex chromosomes in developmental and/or adult effects of testosterone on abdominal aortic AT1 aR expression and Angll-induced AAAs ..