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

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Angiogenesis, the formation of new blood vessels, is crucial for development and wound healing.
• Aberrant angiogenesis is implicated in various diseases, including cancer and rheumatoid arthritis.
• Visfatin is an adipokine with reported pro-angiogenic properties, but its underlying mechanisms are not fully understood.

Purpose of the Study:

• To elucidate the role of Notch1 signaling in visfatin-induced angiogenesis.
• To identify potential downstream target genes regulated by visfatin through Notch1.
• To investigate the therapeutic potential of targeting the visfatin-Notch1 axis in pathological angiogenesis.

Main Methods:

• Inhibition of Notch signaling using pharmacological inhibitors and small interfering RNA (siRNA).
• Assessment of angiogenesis in vitro (endothelial tube formation), ex vivo (aortic ring assay), and in vivo (Matrigel plug assay).
• Analysis of gene expression (Hes1, FGF-2) and protein activation (Notch1 cleavage) using quantitative PCR, Western blotting, and reporter assays.
• Chromatin immunoprecipitation (ChIP) to confirm Notch1 binding to the FGF-2 promoter.

Main Results:

• Notch1 signaling inhibition attenuated visfatin-induced angiogenesis across all tested models.
• Visfatin treatment increased Notch1 activation, Hes1 gene induction, and γ-secretase activity.
• Visfatin stimulated fibroblast growth factor-2 (FGF-2) expression in a Notch1-dependent manner.
• Notch1 directly bound to the CSL-binding site on the FGF-2 promoter in response to visfatin.

Conclusions:

• This study demonstrates Notch1-dependent induction of FGF-2 by visfatin, leading to endothelial angiogenesis.
• The findings reveal Notch1 activation as a key event in visfatin-stimulated angiogenesis.
• The visfatin/Notch1/FGF-2 signaling axis represents a promising therapeutic target for treating pathological angiogenesis.