Specific activation of insulin-like growth factor-1 receptor by ginsenoside Rg5 promotes angiogenesis and vasorelaxation [Signal Transduction]

November 12th, 2014 by Cho, Y.-L., Hur, S.-M., Kim, J.-Y., Kim, J.-H., Lee, D.-K., Choe, J., Won, M.-H., Ha, K.-S., Jeoung, D., Han, S., Ryoo, S., Lee, H., Min, J.-K., Kwon, Y.-G., Kim, D.-H., Kim, Y.-M.

Ginsenoside Rg5 is a compound newly synthesized during the steaming process of ginseng, however, its biological activity has not been elucidated with regard to endothelial function. We found that Rg5 stimulated in vitro angiogenesis of human endothelial cells, consistent with increased neovascularization and blood perfusion in a mouse hindlimb ischemia model. Rg5 also evoked vasorelaxation in aortic rings isolated from wild type and high cholesterol-fed ApoE-/- mice, but not from endothelial nitric oxide synthase (eNOS) knockout mice. Angiogenic activity of Rg5 was highly associated with a specific increase in insulin-like growth factor-1 receptor (IGF-1R) phosphorylation and subsequent activation of multiple angiogenic signals, including ERK, FAK, Akt/eNOS/nitric oxide (NO), and Gi-mediated phospholipase C/Ca2+/eNOS dimerization pathways. The vasodilative activity of Rg5 was mediated by the eNOS/NO/cGMP axis. IGF-1R knockdown suppressed Rg5-induced angiogenesis and vasorelaxation by inhibiting key angiogenic signaling and NO/cGMP pathways. In silico docking analysis showed that Rg5 bound with high affinity to IGF-1R at the same binding site of insulin-like growth factor (IGF). Rg5 blocked binding of IGF-1 to its receptor with an IC50 of ~90 nmol/L. However, Rg5 did not induce vascular inflammation and permeability. These data suggest that Rg5 plays a novel role of an IGF-1R agonist, promoting therapeutic angiogenesis and improving hypertension without adverse effects in the vasculature.
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