Male gender is one of the strongest risk factors in the development of abdominal aortic aneurysms (AAAs). Our results demonstrate a 3-fold greater incidence of angiotensin II (Angll)-induced AAAs in male ApoE-/- mice compared to females. Ovariectomy did not influence Angll-induced AAAs. In contrast, orchiectomy reduced AAA incidence to the level observed in females. These results demonstrate that male sex hormones mediate gender differences in Angll-induced AAAs. Additional data demonstrate greater Angll receptor density and responsiveness in the abdominal aorta of male than female mice. We hypothesize that during development, androgen localizes the AT1a receptor to vascular smooth muscle cells of the abdominal aorta of male mice and continues to increase AT1a receptor expression in cell types critical to the formation of AAAs in adult male mice.
In Specific Aim 1, we will determine the temporal effect of exogenous testosterone administration on AAA formation and localization. The effect of exogenous testosterone in orchiectomized male and in female mice on Angll-induced AAAs will be determined. A focus will be on regulation of the AT1a receptor in the abdominal aorta of male1 and female mice administered testosterone.
In Specific Aim 2, we will determine the cell type mediating androgen receptor effects on AAA formation. The effect of whole body androgen receptor deficiency on Angll-induced AAAs will be examined in male mice. Since macrophages and smooth muscle are involved early in Angll-induced AAAs, we will determine the effect of deficiency of androgen receptors on bone marrow-derived cells and on smooth muscle on Angllinduced AAAs. Additional studies will define mechanisms for androgen regulation of the AT1a receptor promoter.
In Specific Aim 3, we hypothesize that in utero developmental effects of androgen on the mesenchyme give rise to AT1a receptors on vascular smooth muscle cells of the abdominal aorta in adult male mice, thereby localizing AAAs to this region. We will determine the effect of androgen ablation in utero in males, and testosterone administration to neonatal female mice on Angll-induced AAAs in adult offspring. Results from these studies will identify mechanisms for gender differences in AAA formation.
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