Prostanoid-dependent abdominal aortic aneurysm formation

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DESCRIPTION (provided by applicant): Our recent report together with our preliminary studies show that genetic or pharmacological inactivation of cyclooxygenase-2 (COX-2) reduces the incidence and severity of AAAs in mice chronically infused with angiotensin II (Angll). Furthermore, significant COX-2 expression is increased in AAAs as compared to the uninvolved aorta. Our preliminary studies also show that the expression of the PGE2 receptor EP4 is significantly increased in aneurysmal tissue. However, the role of the prostanoid receptors in AAA formation is not clearly defined. The long-term objectives of this proposal are to elucidate mechanisms by which prostanoids contribute to AAAs. We propose the hypothesis that COX-2 participates in all stages of Angll- induced AAA development through preferential synthesis of PGE2 and TXA2 which specifically activate EP4 and TP receptors, respectively. This hypothesis is based on previous observations that a) Explant cultures from human AAAs express significant levels of COX-2. b) PGE2 contributes to vascular pathology by increasing expression and/or activation of matrix metalloproteinases and inducing smooth muscle cell apoptosis. c) TXA2 increases adhesion molecule expression and contributes to influx of macrophages in the vessel wall. Therefore, we propose the following specific aims: 1) Determine the role of COX-2 at multiple stages of AAA formation. These studies will use mice genetically deficient in COX-2 as well as the COX-2- specific inhibitor, celecoxib. 2) Determine the effect of genetic deficiency of the prostanoid receptors, EP4 and TP, on AAA formation. These studies will provide a mechanistic view of the role of COX-2-dependent prostanoids, and will provide insight into the development of novel therapeutics for AAAs. The objectives of the proposed studies are to identify new treatments for abdominal aortic aneurysms (AAAs). AAAs are a life-threatening disease which afflict approximately 5% of the male population over the age of 65, and once the disease has formed, there is an increased chance for rupture of the aorta, an event which most people do not survive. The cause of aortic aneurysms in humans is not known but is thought to involve inflammation within the wall of the aorta. Therefore, we will use an animal model of this disease to determine the mechanisms by which this disease occurs in humans. These studies are important as they will help identify non-surgical treatments for this disease in humans.