Notch1 mediates visfatin-induced FGF-2 up-regulation and endothelial angiogenesis

作者：Bae Yun Hee; Park Hyun Joo; Kim Su Ryun; Kim Jee Young; Kang Youra; Kim Jung Ae; Wee Hee Jun; Kageyama Ryoichiro; Jung Jin Sup; Bae Moon Kyoung; Bae Soo Kyung^*

来源：Cardiovascular Research, 2011, 89(2): 436-445.

DOI：10.1093/cvr/cvq276

• Visfatin
• Notch1
• FGF-2
• Angiogenesis
• Endothelial cells

Aims Our aims were to determine the role of Notch1 in mediating visfatin-induced angiogenesis and to explore potential target genes involved.
Methods and results Inhibition of Notch signalling attenuated visfatin-induced angiogenesis in vitro, ex vivo, and in vivo. Visfatin increased gamma-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.
Conclusion 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.

• 出版日期2011-2