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-Guen Kwon, Eun Bo Shim, Young Myeong Kim

Research output: Contribution to journalArticle

66 Citations (Scopus)

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

Fingerprint

Phosphatidylinositol 3-Kinase
Nitric Oxide Synthase Type III
Colforsin
Vascular Endothelial Growth Factor A
Phosphorylation
Proteins
Mitogen-Activated Protein Kinase Kinases
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
MAP Kinase Signaling System
Crowns
Adenylyl Cyclases
Small Interfering RNA
Endothelial Cells

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Namkoong, Seung ; Kim, Chun Ki ; Cho, Young Lai ; Kim, Ji Hee ; Lee, Hansoo ; Ha, Kwon Soo ; Choe, Jongseon ; Kim, Pyeung Hyeun ; Won, Moo Ho ; Kwon, Young-Guen ; Shim, Eun Bo ; Kim, Young Myeong. / Forskolin increases angiogenesis through the coordinated cross-talk of PKA-dependent VEGF expression and Epac-mediated PI3K/Akt/eNOS signaling. In: Cellular Signalling. 2009 ; Vol. 21, No. 6. pp. 906-915.
@article{91df538c9f8f4de5ba5ca36b5cc9ee08,
title = "Forskolin increases angiogenesis through the coordinated cross-talk of PKA-dependent VEGF expression and Epac-mediated PI3K/Akt/eNOS signaling",
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",
author = "Seung Namkoong and Kim, {Chun Ki} and Cho, {Young Lai} and Kim, {Ji Hee} and Hansoo Lee and Ha, {Kwon Soo} and Jongseon Choe and Kim, {Pyeung Hyeun} and Won, {Moo Ho} and Young-Guen Kwon and Shim, {Eun Bo} and Kim, {Young Myeong}",
year = "2009",
month = "6",
day = "1",
doi = "10.1016/j.cellsig.2009.01.038",
language = "English",
volume = "21",
pages = "906--915",
journal = "Cellular Signalling",
issn = "0898-6568",
publisher = "Elsevier Inc.",
number = "6",

}

Forskolin increases angiogenesis through the coordinated cross-talk of PKA-dependent VEGF expression and Epac-mediated PI3K/Akt/eNOS signaling. / Namkoong, Seung; Kim, Chun Ki; Cho, Young Lai; Kim, Ji Hee; Lee, Hansoo; Ha, Kwon Soo; Choe, Jongseon; Kim, Pyeung Hyeun; Won, Moo Ho; Kwon, Young-Guen; Shim, Eun Bo; Kim, Young Myeong.

In: Cellular Signalling, Vol. 21, No. 6, 01.06.2009, p. 906-915.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Forskolin increases angiogenesis through the coordinated cross-talk of PKA-dependent VEGF expression and Epac-mediated PI3K/Akt/eNOS signaling

AU - Namkoong, Seung

AU - Kim, Chun Ki

AU - Cho, Young Lai

AU - Kim, Ji Hee

AU - Lee, Hansoo

AU - Ha, Kwon Soo

AU - Choe, Jongseon

AU - Kim, Pyeung Hyeun

AU - Won, Moo Ho

AU - Kwon, Young-Guen

AU - Shim, Eun Bo

AU - Kim, Young Myeong

PY - 2009/6/1

Y1 - 2009/6/1

N2 - 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

AB - 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

UR - http://www.scopus.com/inward/record.url?scp=62749171705&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=62749171705&partnerID=8YFLogxK

U2 - 10.1016/j.cellsig.2009.01.038

DO - 10.1016/j.cellsig.2009.01.038

M3 - Article

VL - 21

SP - 906

EP - 915

JO - Cellular Signalling

JF - Cellular Signalling

SN - 0898-6568

IS - 6

ER -