Grants and Contracts Details
Abdominal aortic aneurysms (AAA) account for 2% of deaths and thus are among the 15 leading causes of mortality in the United States. There is no effective pharmacologic treatment for AAA. In humans, males have a much higher incidence of AAAs than females. Our laboratories have shown that chronic infusion of angiotensin II (Angil) into hyperlipidemic mice results in the formation of AAA5 and this experimental model demonstrates a similar higher prevalence of AAAs in male compared to female mice. Castration of male mice reduced AAAs, supporting a primary role for androgen. Recent studies demonstrate that angiotensin type la receptors (AT1aR) are required to initiate Angli induced atherosclerosis and AAAs in ApoE-/- mice. Preliminary data demonstrate that androgen increases AT1aR mRNA expression in abdominal, but not in thoracic aortas from castrated male and female apolipoprotein E (apoE)-I- mice. Moreover, administration of androgen restored MA formation in castrated male, and in female apoE-/- mice. Vascular smooth muscle cells (VSMC) in aortic regions differ in embryonic origin, derived from the lateral mesenctiyme in the abdominal aorta. Moreover, mesenchymal cells exhibit androgen receptor sensitivity during development. Preliminary data support regulation of All aR in abdominal aortas by manipulation of androgen during gestation and development. We hypothesize that during development androgen regulates the expression of the All aR in mesenchymal cells that populate VSMCs in abdominal aortas of male mice, thereby contributing to MA susceptibility in males. In specific aim 1, we will define the role of androgen during development in localizing the All aR to abdominal aortic VSMCs by (a) determining the effect of short term androgen ablation in utero on Angil-induced AMs in male offspring; (b) determining the effect of neonatal androgenization with testosterone on Angli-induced AAAs in female mice. In specific aim 2, we will determine the effect of an androgen receptor antagonist on the formation and progression of AnglI-induced AAAs in male ApoE-/- mice. Results from these studies will identify mechanisms contributing to gender differences in AAAs and suggest new possible therapeutic strategies for treatment of AMs.
|Effective start/end date||7/1/08 → 6/30/10|
- American Heart Association Great Rivers Affiliate: $42,000.00
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