Grants and Contracts Details
Description
Abdominal aortic aneurysms (AAAs) are a common life-threatening disorder with no therapeutic
strategies that effectively blunt growth and progression of the disease. Male sex is a strong risk
factor for AAAs. Similarly, AAAs induced by infusion of angiotensin II (AngII) exhibit marked
sexual dimorphism with a 4-fold higher prevalence in male compared to female mice. Previous
results demonstrated that testosterone exhibits region-specific regulation of angiotensin type 1a
receptor (AT1aR) expression in abdominal aortas to promote AngII-induced AAAs. We also
demonstrated that exposures of neonatal females to testosterone induced permanent increases
in adult susceptibility to AAAs. This model of female androgenization, which mimics surges in
testosterone shortly after birth in males, resulted in increased AT1aR expression in abdominal
aortas and markedly enhanced AAA susceptibility of adult females. Since males require
continued testosterone exposures to exhibit high AAA susceptibility, our results demonstrate
that males and females respond differently to testosterone during development. We propose
that sex hormones, as well as sex chromosomes, mediate sexual dimorphism of AngII-induced
AAAs. 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 regionspecific
increases in aortic AT1aR expression and AngII-induced AAAs. Aim 1 will define the
cell-specific role of androgen receptors in developmental and/or adult effects of testosterone on
abdominal aortic AT1aR expression and AngII-induced AAAs. Aim 2 will define the relative
contribution of sex hormones versus sex chromosomes in developmental and/or adult effects of
testosterone on abdominal aortic AT1aR expression and AngII-induced AAAs. In both aims,
approaches will include studies designed to quantify effects on AAA formation versus
progression. In addition to identifying mechanisms for sexual dimorphism of AngII-induced
AAAs, results from these studies may identify targets, amenable to therapy, that either protect
(females) or augment (males) AAA susceptibility.
Status | Finished |
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Effective start/end date | 3/21/12 → 2/28/13 |
Funding
- National Heart Lung and Blood Institute: $423,666.00
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