The hedgehog transcription factor Gli3 modulates angiogenesis

Marie Ange Renault, Jérôme Roncalli, Jörn Tongers, Sol Misener, Tina Thorne, Kentaro Jujo, Aiko Ito, Trevor Clarke, Chris Fung, Meredith Millay, Christine Kamide, Andrew Scarpelli, Ekaterina Klyachko, Douglas W. Losordo

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

RATIONALE: 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. METHODS AND 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.

Original languageEnglish (US)
Pages (from-to)818-826
Number of pages9
JournalCirculation research
Volume105
Issue number8
DOIs
StatePublished - Oct 2009

Keywords

  • Angiogenesis
  • Endothelial cells
  • Gli transcription factors
  • Ischemia
  • Myocardial infarction
  • Sonic Hedgehog

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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