Androgen Regulation of Angiotensin Responses in Aneurysms

University Of Kentucky, Lexington KY

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Abstract

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