title: PGE(2) -EP(2) signalling in endothelium is activated by haemodynamic stress and induces cerebral aneurysm through an amplifying loop via NF-κB.
abstract: OBJECTIVE
  Cerebral aneurysm is a frequent cerebrovascular event and a major cause of fatal subarachnoid haemorrhage, but there is no medical treatment for this condition. Haemodynamic stress and, recently, chronic inflammation have been proposed as major causes of cerebral aneurysm. Nevertheless, links between haemodynamic stress and chronic inflammation remain ill-defined, and to clarify such links, we evaluated the effects of prostaglandin E(2) (PGE(2) ), a mediator of inflammation, on the formation of cerebral aneurysms.
  
  
  METHODS
  Expression of COX and prostaglandin E synthase (PGES) and PGE receptors were examined in human and rodent cerebral aneurysm. The incidence, size and inflammation of cerebral aneurysms were evaluated in rats treated with COX-2 inhibitors and mice lacking each prostaglandin receptor. Effects of shear stress and PGE receptor signalling on expression of pro-inflammatory molecules were studied in primary cultures of human endothelial cells (ECs).
  
  
  RESULTS
  COX-2, microsomal PGES-1 and prostaglandin E receptor 2 (EP(2) ) were induced in ECs in the walls of cerebral aneurysms. Shear stress applied to primary ECs induced COX-2 and EP(2) . Inhibition or loss of COX-2 or EP(2) in vivo attenuated each other's expression, suppressed nuclear factor κB (NF-κB)-mediated chronic inflammation and reduced incidence of cerebral aneurysm. EP(2) stimulation in primary ECs induced NF-κB activation and expression of the chemokine (C-C motif) ligand 2, essential for cerebral aneurysm.
  
  
  CONCLUSIONS
  These results suggest that shear stress activated PGE(2) -EP(2) pathway in ECs and amplified chronic inflammation via NF-κB. We propose EP(2) as a therapeutic target in cerebral aneurysm.
authors.affiliation: Department of Neurosurgery Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Aoki
authors.forename: M
authors.initials: M
authors.lastname: Nishimura
authors.forename: T
authors.initials: T
authors.lastname: Matsuoka
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: T
authors.initials: T
authors.lastname: Furuyashiki
authors.forename: H
authors.initials: H
authors.lastname: Kataoka
authors.forename: S
authors.initials: S
authors.lastname: Kitaoka
authors.forename: R
authors.initials: R
authors.lastname: Ishibashi
authors.forename: A
authors.initials: A
authors.lastname: Ishibazawa
authors.forename: S
authors.initials: S
authors.lastname: Miyamoto
authors.forename: R
authors.initials: R
authors.lastname: Morishita
authors.forename: J
authors.initials: J
authors.lastname: Ando
authors.forename: N
authors.initials: N
authors.lastname: Hashimoto
authors.forename: K
authors.initials: K
authors.lastname: Nozaki
authors.forename: S
authors.initials: S
authors.lastname: Narumiya
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D002532:Intracranial Aneurysm / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018932:Chemokine CCL2; D052246:Cyclooxygenase 2 Inhibitors; D016328:NF-kappa B; D058307:Receptors, Prostaglandin E, EP2 Subtype; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone