Abdominal aortic aneurysms (AAAs) are a common life-threatening disorder with no therapeutic strategies that effectively blunt growth and progression of the disease. Male sex is a strong risk factor for AAAs. Similarly, AAAs induced by infusion of angiotensin II (AngII) exhibit marked sexual dimorphism with a 4-fold higher prevalence in male compared to female mice. Previous results demonstrated that testosterone exhibits region-specific regulation of angiotensin type 1a receptor (AT1aR) expression in abdominal aortas to promote AngII-induced AAAs. We also demonstrated that exposures of neonatal females to testosterone induced permanent increases in adult susceptibility to AAAs. This model of female androgenization, which mimics surges in testosterone shortly after birth in males, resulted in increased AT1aR expression in abdominal aortas and markedly enhanced AAA susceptibility of adult females. Since males require continued testosterone exposures to exhibit high AAA susceptibility, our results demonstrate that males and females respond differently to testosterone during development. We propose that sex hormones, as well as sex chromosomes, mediate sexual dimorphism of AngII-induced AAAs. The central hypothesis of this proposal is that testosterone effects (developmental and/or adult) at pivotal cell types, in addition to sex chromosome effects, promote region- specific increases in aortic AT1aR expression and AngII-induced AAAs.
Aim 1 will define the cell-specific role of androgen receptors in developmental and/or adult effects of testosterone on abdominal aortic AT1aR expression and AngII-induced AAAs.
Aim 2 will define the relative contribution of sex hormones versus sex chromosomes in developmental and/or adult effects of testosterone on abdominal aortic AT1aR expression and AngII-induced AAAs. In both aims, approaches will include studies designed to quantify effects on AAA formation versus progression. In addition to identifying mechanisms for sexual dimorphism of AngII-induced AAAs, results from these studies may identify targets, amenable to therapy, that either protect (females) or augment (males) AAA susceptibility.

Public Health Relevance

The proposed research will define mechanisms for sex differences in susceptibility to abdominal aortic aneurysms (AAAs). A unique and relevant aspect of these studies is a focus on effects of male sex hormone exposures during development as a mediator of greater susceptibility to AAAs in adult males. This shift in focus to development may identify novel interventions early in life that can prevent or decrease vascular disease in aging males and females. In addition, these are the first studies to define the role of sex chromosomes as mediators of the pronounced sexual dimorphism in AAA formation and/or progression.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-VH-D (90))
Program Officer
Reid, Diane M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kentucky
Schools of Medicine
United States
Zip Code
Robinet, Peggy; Milewicz, Dianna M; Cassis, Lisa A et al. (2018) Consideration of Sex Differences in Design and Reporting of Experimental Arterial Pathology Studies-Statement From ATVB Council. Arterioscler Thromb Vasc Biol 38:292-303
Alsiraj, Yasir; Thatcher, Sean E; Blalock, Eric et al. (2018) Sex Chromosome Complement Defines Diffuse Versus Focal Angiotensin II-Induced Aortic Pathology. Arterioscler Thromb Vasc Biol 38:143-153
Arnold, Arthur P; Cassis, Lisa A; Eghbali, Mansoureh et al. (2017) Sex Hormones and Sex Chromosomes Cause Sex Differences in the Development of Cardiovascular Diseases. Arterioscler Thromb Vasc Biol 37:746-756
Alsiraj, Yasir; Thatcher, Sean E; Charnigo, Richard et al. (2017) Female Mice With an XY Sex Chromosome Complement Develop Severe Angiotensin II-Induced Abdominal Aortic Aneurysms. Circulation 135:379-391
Davis, Frank M; Rateri, Debra L; Balakrishnan, Anju et al. (2015) Smooth muscle cell deletion of low-density lipoprotein receptor-related protein 1 augments angiotensin II-induced superior mesenteric arterial and ascending aortic aneurysms. Arterioscler Thromb Vasc Biol 35:155-62
Lu, Hong; Howatt, Deborah A; Balakrishnan, Anju et al. (2015) Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice. J Vis Exp :
Liu, Jing; Lu, Hong; Howatt, Deborah A et al. (2015) Associations of ApoAI and ApoB-containing lipoproteins with AngII-induced abdominal aortic aneurysms in mice. Arterioscler Thromb Vasc Biol 35:1826-34
Zhang, Xuan; Thatcher, Sean; Wu, Congqing et al. (2015) Castration of male mice prevents the progression of established angiotensin II-induced abdominal aortic aneurysms. J Vasc Surg 61:767-76
Rateri, Debra L; Davis, Frank M; Balakrishnan, Anju et al. (2014) Angiotensin II induces region-specific medial disruption during evolution of ascending aortic aneurysms. Am J Pathol 184:2586-95
Thatcher, Sean E; Zhang, Xuan; Howatt, Deborah A et al. (2014) Angiotensin-converting enzyme 2 decreases formation and severity of angiotensin II-induced abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 34:2617-23

Showing the most recent 10 out of 14 publications