Forskolin increases angiogenesis through the coordinated cross-talk of PKA-dependent VEGF expression and Epac-mediated PI3K/Akt/eNOS signaling

Seung Namkoong, Chun Ki Kim, Young Lai Cho, Ji Hee Kim, Hansoo Lee, Kwon Soo Ha, Jongseon Choe, Pyeung Hyeun Kim, Moo Ho Won, Young Geun Kwon, Eun Bo Shim, Young Myeong Kim

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Abstract

Forskolin, a potent activator of adenylyl cyclases, has been implicated in modulating angiogenesis, but the underlying mechanism has not been clearly elucidated. We investigated the signal mechanism by which forskolin regulates angiogenesis. Forskolin stimulated angiogenesis of human endothelial cells and in vivo neovascularization, which was accompanied by phosphorylation of CREB, ERK, Akt, and endothelial nitric oxide synthase (eNOS) as well as NO production and VEGF expression. Forskolin-induced CREB phosphorylation, VEGF promoter activity, and VEGF expression were blocked by the PKA inhibitor PKI. Moreover, phosphorylation of ERK by forskolin was inhibited by the MEK inhibitor PD98059, but not PKI. The forskolin-induced Akt/eNOS/NO pathway was completely inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, but not significantly suppressed by PKI. These inhibitors and a NOS inhibitor partially inhibited forskolin-induced angiogenesis. The exchange protein directly activated by cAMP (Epac) activator, 8CPT-2Me-cAMP, promoted the Akt/eNOS/NO pathway and ERK phosphorylation, but did not induce CREB phosphorylation and VEGF expression. The angiogenic effect of the Epac activator was diminished by the inhibition of PI3K and MEK, but not by the PKA inhibitor. Small interfering RNA-mediated knockdown of Epac1 suppressed forskolin-induced angiogenesis and phosphorylation of ERK, Akt, and eNOS, but not CREB phosphorylation and VEGF expression. These results suggest that forskolin stimulates angiogenesis through coordinated cross-talk between two distinct pathways, PKA-dependent VEGF expression and Epac-dependent ERK activation and PI3K/Akt/eNOS/NO signaling. Crown

Original languageEnglish
Pages (from-to)906-915
Number of pages10
JournalCellular Signalling
Volume21
Issue number6
DOIs
Publication statusPublished - 2009 Jun 1

All Science Journal Classification (ASJC) codes

  • Cell Biology

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    Namkoong, S., Kim, C. K., Cho, Y. L., Kim, J. H., Lee, H., Ha, K. S., Choe, J., Kim, P. H., Won, M. H., Kwon, Y. G., Shim, E. B., & Kim, Y. M. (2009). Forskolin increases angiogenesis through the coordinated cross-talk of PKA-dependent VEGF expression and Epac-mediated PI3K/Akt/eNOS signaling. Cellular Signalling, 21(6), 906-915. https://doi.org/10.1016/j.cellsig.2009.01.038