Deletion of EP4 on bone marrow-derived cells enhances inflammation and angiotensin II-induced abdominal aortic aneurysm formation

Abstract

Objective-: To examine whether a lack of prostaglandin E receptor 4 (EP4) on bone marrow-derived cells would increase local inflammation and enhance the formation of abdominal aortic aneurysm (AAA) in vivo. Methods and results-: Prostaglandin E2 (PGE2) through activation of EP4, can mute inflammation. Hypercholesterolemic low-density lipoprotein receptor knockout (LDLR) mice transplanted with either EP4 (EP4/LDLR) or EP4 (EP4/LDLR) bone marrow received infusions of angiotensin II to induce AAA. Deficiency of EP4 on bone marrow-derived cells increased the incidence (50% of male EP4/LDLR mice versus 88.9% of male EP4/LDLR mice developed AAA; and 22% of female EP4/LDLR mice versus 83.3% of female EP4/LDLR mice developed AAA) and severity of AAA, increased monocyte chemoattractant protein-1 (2.72-fold in males and 1.64-fold in females), and enhanced infiltration of macrophages (3.8-fold in males and 2.44-fold in females) and T cells (1.88-fold in males and 1.66-fold in females) into AAA lesions. Lack of EP4 on bone marrow-derived cells augmented elastin fragmentation, increased apoptotic markers, and decreased smooth muscle cell accumulation within AAA lesions. Conclusion-: Deficiency of EP4 on bone marrow-derived cells boosted inflammation and AAA formation induced by angiotensin II in hyperlipidemic mice. This study affirms the pathophysiologic importance of PGE2 signaling through EP4 as an endogenous anti-inflammatory pathway involved in experimental aneurysm formation. © 2011 American Heart Association, Inc.