Grants and Contracts Details
Description
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.
Status | Finished |
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Effective start/end date | 7/1/08 → 6/30/10 |
Funding
- American Heart Association Great Rivers Affiliate: $42,000.00
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