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Arterioscler Thromb Vasc Biol. 2011 Feb;31(2):261-9. doi: 10.1161/ATVBAHA.110.216580. Epub 2010 Nov 18.

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

Author information

1
Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Ave. Louis Pasteur, Boston, MA 02115, USA.

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 E(2) (PGE(2)) 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.

CONCLUSIONS:

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 PGE(2) signaling through EP4 as an endogenous anti-inflammatory pathway involved in experimental aneurysm formation.

PMID:
21088251
PMCID:
PMC3025710
DOI:
10.1161/ATVBAHA.110.216580
[Indexed for MEDLINE]
Free PMC Article

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