ProstaglandinE2-EP4 Axis and AngiotensinII-Induced Abdominal Aortic Aneurysms

Cardiovascular diseases including abdominal aortic aneurysms (AAAs), are often characterized by increased formation of prostanoid mediators of inflammation. Preliminary studies demonstrate that selective pharmacological inhibition of cyclooxygenase-2 (COX-2) markedly attenuated the incidence and severity of AAAs in mice chronically infused with angiotensin II (Angll). One of the earliest events in Angll-induced AAA formation is the degradation of elastin in media of the abdominal aorta, with coincident infiltration of macrophages into the media. Matrix metalloproteinases (MMPs) are a potential class of mediators that could playa role in the degradation of medial elastin leading to the formation and progression of AAAs. There is abundant evidence for the presence of selected MMPs in human AAAs. The broad spectrum MMP inhibitor doxycycline attenuated AAA formation in Angll-infused mice, suggesting that MMPs playa critical role in AAA formation. The inhibition of aortic expansion by a non-selective COX inhibitor was associated with a decrease in COX-2 expression, prostaglandin E2 (PGE2) concentration, and MMP activation in a rat model of AAA formation. However, the role of PGE2 in mediating increases in MMP expression and activity in Angll-induced AM formation remains to be defined. PGE2 mediates its effects by binding to the EP receptor. The long-term objective of this proposal is to elucidate the role of the PGE2-EP4 axis in Angll-induced MA formation. We propose the hypothesis that PGE2 acting through the EP4 receptor mediates the initial stage of Angll-induced AM formation. To test this hypothesis we propose the following specific aims: 1) Determine the role of the PGE2-EP4 axis in MMP expression and activation in macrophage and vascular smooth muscle cells. 2) Determine if the macrophage EP4 receptor is critical for the development of Angll-induced MAs in apoE-/- mice. These studies will provide a mechanistic insight into the role of PGE2 and EP4 in the development AMs and valuable information for the development of novel therapeutics for treatment this disease.