Gender Differences in Experimental Aortic Aneurysms

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DESCRIPTION (provided by applicant): 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. 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 aforementioned specific soluble mediator dependent leukocyte trafficking, ultimately driving the balance of matrix degradation and repair toward aneurysm formation.