Deficiency of EP4 receptor on bone marrowderived cells boosted inflammation and abdominal aortic aneurysm formation induced by angiotensin II in hyperlipidemic mice

Abstract

Objective: Chronic inflammation during abdominal aortic aneurysm (AAA) formation contributes to remodeling and eventual weakening of the vessel wall. Prostaglandin E2 (PGE2), through activation of its receptor EP4, can mute inflammation. Whether EP4 participates directly in the pathogenesis of aneurysm remains unknown. We tested the hypothesis that a lack of EP4 receptor on bone marrow-derived cells would increase local inflammation and enhance the formation of AAA in vivo. Methods and Results: Hypercholesterolemic low-density lipoprotein receptor knockout (LDLR-/-) mice transplanted with either EP4+/+ [EP4+/+/LDLR-/-] or EP4-/- [EP-/-/LDLR-/-] bone marrow received infusions of angiotensin II to induce AAA. Deficiency of EP4 on bone marrow-derived cells increased the incidence and severity of AAA, increased monocyte chemoattractant protein-1 (MCP-1), and enhanced infiltration of macrophages and T cells into the AAA lesions. Lack of EP4 also augmented elastin fragmentation, increased the number of cells bearing markers of apoptosis, and decreased smooth-muscle cell accumulation within the AAA lesions.

Conclusions: Deficiency of EP4 receptor 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 path involved in AAA formation.