The Hedgehog transcription factor Gli3 modulates angiogenesis.
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.
Renault
Marie-Ange
MA
Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, 303 E Chicago Ave., Chicago, IL 60611, USA.
Roncalli
Jérôme
J
Tongers
Jörn
J
Misener
Sol
S
Thorne
Tina
T
Jujo
Kentaro
K
Ito
Aiko
A
Clarke
Trevor
T
Fung
Chris
C
Millay
Meredith
M
Kamide
Christine
C
Scarpelli
Andrew
A
Klyachko
Ekaterina
E
Losordo
Douglas W
DW
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
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