TY - JOUR
T1 - The hedgehog transcription factor Gli3 modulates angiogenesis
AU - Renault, Marie Ange
AU - Roncalli, Jérôme
AU - Tongers, Jörn
AU - Misener, Sol
AU - Thorne, Tina
AU - Jujo, Kentaro
AU - Ito, Aiko
AU - Clarke, Trevor
AU - Fung, Chris
AU - Millay, Meredith
AU - Kamide, Christine
AU - Scarpelli, Andrew
AU - Klyachko, Ekaterina
AU - Losordo, Douglas W.
PY - 2009/10
Y1 - 2009/10
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Endothelial cells
KW - Gli transcription factors
KW - Ischemia
KW - Myocardial infarction
KW - Sonic Hedgehog
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U2 - 10.1161/CIRCRESAHA.109.206706
DO - 10.1161/CIRCRESAHA.109.206706
M3 - Article
C2 - 19729595
AN - SCOPUS:70350129066
SN - 0009-7330
VL - 105
SP - 818
EP - 826
JO - Circulation research
JF - Circulation research
IS - 8
ER -