Year of Publication

2011

Degree Name

Doctor of Philosophy (PhD)

Document Type

Dissertation

College

Medicine

Department

Toxicology

First Advisor

Dr. Lisa Cassis

Abstract

The purpose of this study was to determine whether androgen promotes AT1aR expression on smooth muscle to confer high prevalence of AngII-induced AAAs in hyperlipidemic mice. In addition, we also investigate the role of androgen in the progression of established AngII-induced AAAs.

First, we sought to examine the role of endogenous androgen in the growth of established AngII-induced AAAs. By castrating male mice, we demonstrated that removal of endogenous androgen significantly decreased the progressive lumen dilation of established AngII-induced AAAs in male ApoE-/- mice, but had no effect on external AAA diameters. These results suggest that androgen contributes to the progression of established AAAs through distinct mechanisms that differentially influence aortic lumen and wall diameters.

We also investigate whether androgen regulates aortic AT1aR expression to promote AngII-induced AAA formation. Our data demonstrated that in male and female mice, both endogenous and exogenous androgen stimulate AT1aR level particularly in abdominal aortas. This androgen-dependent enhanced expression of abdominal aortic AT1aR was correlated with increased AngIIinduced AAA formation in male and female mice. Smooth muscle AT1aR deficiency significantly reduced luminal and external diameters of abdominal aortas as well as the incidence of AngII-induced AAAs in adult female mice administered exogenous androgen. Collectively, these results indicate that in adult mice androgen stimulate smooth muscle AT1aR expression to promote AngII-induced AAA formation.

To determine the role of androgen during development on AT1aR expression on SMC and AngII-induced vascular pathologies, we exposed neonatal female mice to one single dose of testosterone. Our data demonstrated that neonatal testosterone administration dramatically increased AngII-induced AAA, atherosclerosis and ascending aortic aneurysms in adult female mice. In addition, smooth muscle AT1aR deficiency reduced effects of neonatal testosterone to promote AAAs, but had no effect on the other two AngII-induced vascular pathologies.

In summary, our findings demonstrated that androgen, both in adult life and during development, stimulate smooth muscle AT1aR expression and promote AngII-induced AAA in female hyperlipidemic mice.

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