title: Importance of endothelial NF-κB signalling in vascular remodelling and aortic aneurysm formation.
abstract: OBJECTIVE
  Vascular remodelling and aortic aneurysm formation are induced mainly by inflammatory responses in the adventitia and media. However, relatively little is known about the mechanistic significance of endothelium in the pathogenesis of these vascular disorders. The transcription factor nuclear factor-kappa B (NF-κB) regulates the expressions of numerous genes, including those related to pro-inflammatory responses. Therefore, to investigate the roles of endothelial pro-inflammatory responses, we examined the impact of blocking endothelial NF-κB signalling on intimal hyperplasia and aneurysm formation.
  
  
  RESULTS
  To block endothelial NF-κB signalling, we used transgenic mice expressing dominant-negative IκBα selectively in endothelial cells (E-DNIκB mice). E-DNIκB mice were protected from the development of cuff injury-induced neointimal formation, in association with suppressed arterial expressions of cellular adhesion molecules, a macrophage marker, and inflammatory factors. In addition, the blockade of endothelial NF-κB signalling prevented abdominal aortic aneurysm formation in an experimental model, hypercholesterolaemic apolipoprotein E-deficient mice with angiotensin II infusion. In this aneurysm model as well, aortic expressions of an adhesion molecule, a macrophage marker, and inflammatory factors were suppressed with the inhibited expression and activity of matrix metalloproteinases in the aorta.
  
  
  CONCLUSIONS
  Endothelial NF-κB activation up-regulates adhesion molecule expression, which may trigger macrophage infiltration and inflammation in the adventitia and media. Thus, the endothelium plays important roles in vascular remodelling and aneurysm formation through its intracellular NF-κB signalling.
authors.affiliation: Department of Metabolic Diseases,  Center for Metabolic Diseases, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575,  Japan.
authors.forename: Tokuo
authors.initials: T
authors.lastname: Saito
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ishigaki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamada
authors.forename: Junhong
authors.initials: J
authors.lastname: Gao
authors.forename: Junta
authors.initials: J
authors.lastname: Imai
authors.forename: Kenji
authors.initials: K
authors.lastname: Uno
authors.forename: Keizo
authors.initials: K
authors.lastname: Kaneko
authors.forename: Takehide
authors.initials: T
authors.lastname: Ogihara
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shimosawa
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Asano
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Oka
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005263:Femoral Artery / Q000276:immunology / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D015398:Signal Transduction; D057772:Vascular System Injuries / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control
chemical_list: D001057:Apolipoproteins E; D015415:Biomarkers; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000804:Angiotensin II; D000072000:NF-KappaB Inhibitor alpha; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse