Leptin-induces Notch expression in endothelial cells through activation of VEGFR-1 and VEGFR-2 in the absence of VEGF. Leptin induces VEGFR-2 expression and transphosphorylation at Y951, Y966, and Y1175, that in turn induces the expression of Notch genes/proteins. These effects of leptin increase endothelial cell proliferation, S-phase progression, and tube formation. Inhibition of OB-R, VEGFR-2 or Notch signaling negatively impacts leptin pro-angiogenic effects in endothelial cells.