Abdominal aortic aneurysms (AAAs) comprise the 10th leading cause of death in Caucasian males 65-74 years of age and accounted for nearly 16,000 deaths overall in the year 2000. Understanding the pathophysiology of AAAs is an important undertaking. Clinically, multiple risk factors are associated with the development of AAAs, including increasing age, positive smoking history, and hypertension. Male gender is also a well-established risk factor for the development of an AAA with a 4:1 male to female ratio. The reason for this gender disparity is unknown. The pathogenesis of AAAs formation is complex and multifactorial. Histologically, AAAs are characterized by early chemokine driven leukocyte infiltration into the aortic wall with subsequent destruction of elastin and collagen in the media and adventitia by excessive local production of matrix degrading enzymes, and smooth muscle cell loss with thinning of the aortic wall. At present, there are no medical therapies available to treat patients with aortic aneurysms, using only the crude measurement of aortic diameter as a threshold for which patients must undergo life-threatening and costly surgery, either open or endovascularly. Therefore, defining the early mechanisms underlying gender-related differences in AAA formation are critical and will be the focus of the present investigation. Understanding differences in disease patterns based on gender may allow us to develop new translational approaches to the prevention and treatment of patients with aortic aneurysms.

Overall Hypothesis
Gender-related differences in aortic aneurysm formation are mediated by the hormonal (androgen: estrogen ratio) regulation of leukocyte trafficking into the aortic wall.

Specific Aim 1. To define the mechanism by which early inflammatory cell recruitment is accelerated in males during AAA formation. Studies will test the hypothesis that increased incidence of AAAs in males is secondary to increased recruitment of leukocytes into the aortic wall driven by an excess of androgens relative to estrogens. Using a reproducible, infrarenal aortic aneurysm model in mice, specific soluble mediators (MIP2, KC GRO, MIP1α, MCP1, TNFα and IL1β), critical during early leukocyte trafficking, will be examined in detail. Bone marrow transplantation will be performed between genders in order to generate functional gender chimeras to access the importance of intrinsic aortic differences versus those that are attributable to the circulating leukocyte. Subsequent experiments using various knockout mice (IL8, CSF1) will extend these initial observations by focusing on the independent roles of the neutrophil and the macrophage during early aneurysm formation. Human aortic tissue will also be used from aneurysm samples, as well as from organ transplant donors, in order to confirm model findings in men and women.

Specific Aim 2. To demonstrate that gonadal hormones can be used to modulate the inflammatory response accompanying AAA formation. Studies will test the hypothesis that altering the androgen: estrogen environment can dictate the prevalence of aneurysm formation by altering the forementioned specific soluble mediator dependent leukocyte trafficking, ultimately driving the balance of matrix degradation (matrix metalloproteinase 9 and 2) and repair (extracellular matrix proteins elastin and collagen) toward aneurysm formation. In these experiments, using surgical, pharmacologic and genetic hormonal manipulation, we will seek to understand the role of gender on intrinsic aortic tissue. Initial experiments in this aim will be carried out using castration, as well as exogenous hormone supplementation (estradiol and testosterone) and inhibition (selective estrogen receptor modulator Tamoxifen, aromatase inhibition Letrozole, antiandrogen Casodex). Knockout mice with decreased circulating estrogen and deficient testosterone will also be examined. Intrinsic differences in male and female aortas will be determined by aortic transplantation. Next, experiments focusing on the various hormone receptors will be performed, using various knockout mice (estrogen α- and β-receptor, androgen receptor). We will also determine whether altering the androgen: estrogen ratio directly alters aortic wall MMP2 and 9 expression and activity, or extracellular matrix (ECM) proteins elastin and collagen; ultimately leading to gender-based differences in AAA formation.

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