title: The Hedgehog transcription factor Gli3 modulates angiogenesis.
abstract: BACKGROUND
  The Gli transcription factors are mediators of Hedgehog (Hh) signaling and have been shown to play critical roles during embryogenesis. Previously, we have demonstrated that the Hh pathway is reactivated by ischemia in adult mammals, and that this pathway can be stimulated for therapeutic benefit; however, the specific roles of the Gli transcription factors during ischemia-induced Hh signaling have not been elucidated.
  
  
  OBJECTIVE
  To investigate the role of Gli3 in ischemic tissue repair.
  
  
  RESULTS
  Gli3-haploinsufficient (Gli3(+/-)) mice and their wild-type littermates were physiologically similar in the absence of ischemia; however, histological assessments of capillary density and echocardiographic measurements of left ventricular ejection fractions were reduced in Gli3(+/-) mice compared to wild-type mice after surgically induced myocardial infarction, and fibrosis was increased. Gli3-deficient mice also displayed reduced capillary density after induction of hindlimb ischemia and an impaired angiogenic response to vascular endothelial growth factor in the corneal angiogenesis model. In endothelial cells, adenovirus-mediated overexpression of Gli3 promoted migration (modified Boyden chamber), small interfering RNA-mediated downregulation of Gli3 delayed tube formation (Matrigel), and Western analyses identified increases in Akt phosphorylation, extracellular signal-regulated kinase (ERK)1/2 activation, and c-Fos expression; however, promoter-reporter assays indicated that Gli3 overexpression does not modulate Gli-dependent transcription. Furthermore, the induction of endothelial cell migration by Gli3 was dependent on Akt and ERK1/2 activation.
  
  
  CONCLUSIONS
  Collectively, these observations indicate that Gli3 contributes to vessel growth under both ischemic and nonischemic conditions and provide the first evidence that Gli3 regulates angiogenesis and endothelial cell activity in adult mammals.
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, 303 E Chicago Ave., Chicago, IL 60611, USA.
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Renault
authors.forename: Jérôme
authors.initials: J
authors.lastname: Roncalli
authors.forename: Jörn
authors.initials: J
authors.lastname: Tongers
authors.forename: Sol
authors.initials: S
authors.lastname: Misener
authors.forename: Tina
authors.initials: T
authors.lastname: Thorne
authors.forename: Kentaro
authors.initials: K
authors.lastname: Jujo
authors.forename: Aiko
authors.initials: A
authors.lastname: Ito
authors.forename: Trevor
authors.initials: T
authors.lastname: Clarke
authors.forename: Chris
authors.initials: C
authors.lastname: Fung
authors.forename: Meredith
authors.initials: M
authors.lastname: Millay
authors.forename: Christine
authors.initials: C
authors.lastname: Kamide
authors.forename: Andrew
authors.initials: A
authors.lastname: Scarpelli
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Klyachko
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000235:genetics; D016762:Genes, fos / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D015398:Signal Transduction; D000074290:Zinc Finger Protein Gli3
chemical_list: C065683:GLI3 protein, human; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000074290:Zinc Finger Protein Gli3; D048052:Mitogen-Activated Protein Kinase 3