title: 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.
  
  
  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.
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Ave. Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Eva H C
authors.initials: EH
authors.lastname: Tang
authors.forename: Eugenia
authors.initials: E
authors.lastname: Shvartz
authors.forename: Koichi
authors.initials: K
authors.lastname: Shimizu
authors.forename: Viviane Z
authors.initials: VZ
authors.lastname: Rocha
authors.forename: Chunyu
authors.initials: C
authors.lastname: Zheng
authors.forename: Daiju
authors.initials: D
authors.lastname: Fukuda
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
authors.forename: Galina
authors.initials: G
authors.lastname: Sukhova
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced* / Q000453:epidemiology / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D018932:Chemokine CCL2 / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006949:Hyperlipidemias / Q000150:complications / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced* / Q000453:epidemiology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C545651:Ptger4 protein, mouse; D011973:Receptors, LDL; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000804:Angiotensin II; D004549:Elastin