title: Endothelial nuclear factor-κB-dependent regulation of arteriogenesis and branching.
abstract: BACKGROUND
  Arteriogenesis and collateral formation are complex processes requiring integration of multiple inputs to coordinate vessel branching, growth, maturation, and network size. Factors regulating these processes have not been determined.
  
  
  RESULTS
  We used an inhibitor of NFκB activation (IκBαSR) under control of an endothelial-specific inducible promoter to selectively suppress endothelial nuclear factor-κB activation during development, in the adult vasculature, or in vitro. Inhibition of nuclear factor-κB activation resulted in formation of an excessively branched arterial network that was composed of immature vessels and provided poor distal tissue perfusion. Molecular analysis demonstrated reduced adhesion molecule expression leading to decreased monocyte influx, reduced hypoxia-inducible factor-1α levels, and a marked decrease in δ-like ligand 4 expression with a consequent decrease in Notch signaling. The latter was the principal cause of increased vascular branching as treatment with Jagged-1 peptide reduced the size of the arterial network to baseline levels.
  
  
  CONCLUSIONS
  These findings identify nuclear factor-κB as a key regulator of adult and developmental arteriogenesis and collateral formation. Nuclear factor-κB achieves this by regulating hypoxia-inducible factor-1α-dependent expression of vascular endothelial growth factor-A and platelet-derived growth factor-BB, which are necessary for the development and maturation of the arterial collateral network, and by regulating δ-like ligand 4 expression, which in turn determines the size and complexity of the network.
authors.affiliation: Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT 06520-8017, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Tirziu
authors.forename: Irina M
authors.initials: IM
authors.lastname: Jaba
authors.forename: Pengchun
authors.initials: P
authors.lastname: Yu
authors.forename: Bruno
authors.initials: B
authors.lastname: Larrivée
authors.forename: Brian G
authors.initials: BG
authors.lastname: Coon
authors.forename: Brunella
authors.initials: B
authors.lastname: Cristofaro
authors.forename: Zhen W
authors.initials: ZW
authors.lastname: Zhuang
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Lanahan
authors.forename: Martin A
authors.initials: MA
authors.lastname: Schwartz
authors.forename: Anne
authors.initials: A
authors.lastname: Eichmann
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000077214:Becaplermin; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D006614:Hindlimb / Q000098:blood supply; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D012160:Retina / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D052002:NF-kappa B p50 Subunit; D020574:Proto-Oncogene Proteins c-sis; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000077214:Becaplermin