Notch1 mediates visfatin-induced FGF-2 up-regulation and endothelial angiogenesis.
OBJECTIVE
Our aims were to determine the role of Notch1 in mediating visfatin-induced angiogenesis and to explore potential target genes involved.


RESULTS
Inhibition of Notch signalling attenuated visfatin-induced angiogenesis in vitro, ex vivo, and in vivo. Visfatin increased γ-secretase activity, Notch1 cleavage and activation, and Hes1 gene induction. Visfatin also stimulated fibroblast growth factor-2 (FGF-2) gene expression in a Notch1-dependent manner. Enforced expression of active Notch1 intracellular domain increased FGF-2 protein levels and stimulated endothelial tube formation, whereas blocking Notch1 signalling or knockdown of Notch1 by small interfering RNA suppressed visfatin-induced FGF-2 up-regulation and angiogenesis. Reporter analysis of FGF-2 promoter revealed the presence of CSL (CBF-1, suppressor of hairless, LAG-1)-binding site, and chromatin immunoprecipitation analysis demonstrated the binding of Notch1-CSL complex to this site in response to visfatin.


CONCLUSIONS
Our data provide the first example of Notch1-dependent endothelial FGF-2 induction by visfatin and of Notch1 activation in visfatin-stimulated endothelial angiogenesis, suggesting that the signalling axis of visfatin/Notch1/angiogenic factors like FGF-2 might be a valuable target for pathological angiogenesis.
Bae
Yun-Hee
YH
Department of Physiology, School of Medicine, Yangsan Campus of Pusan National University, Yangsan 626-870, Republic of Korea.
Park
Hyun-Joo
HJ
Kim
Su-Ryun
SR
Kim
Jee-Young
JY
Kang
Youra
Y
Kim
Jung-Ae
JA
Wee
Hee-Jun
HJ
Kageyama
Ryoichiro
R
Jung
Jin Sup
JS
Bae
Moon-Kyoung
MK
Bae
Soo-Kyung
SK
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001665:Binding Sites; D002478:Cells, Cultured; D002642:Chick Embryo; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D014162:Transfection; D015854:Up-Regulation
D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D004151:Dipeptides; D004791:Enzyme Inhibitors; D016222:Fibroblast Growth Factor 2; D018398:Homeodomain Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D054409:Nicotinamide Phosphoribosyltransferase; D051881:Receptor, Notch1; D011994:Recombinant Proteins; D000072056:Transcription Factor HES-1; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497761:NOTCH1 protein, human; C497570:RBPJ protein, human; C078493:HES1 protein, human; C085455:nicotinamide phosphoribosyltransferase, human