福斯科林
血管生成
蛋白激酶B
MAPK/ERK通路
磷酸化
奶油
PI3K/AKT/mTOR通路
伊诺斯
化学
激活剂(遗传学)
MEK抑制剂
信号转导
LY294002型
细胞生物学
癌症研究
生物
内分泌学
一氧化氮合酶
转录因子
生物化学
一氧化氮
刺激
基因
作者
Seung Namkoong,CK Kim,Young-Lai Cho,Jihee Kim,Hansoo Lee,Kwon‐Soo Ha,Jongseon Choe,Pyeung-Hyeun Kim,Moo‐Ho Won,Young-Geun Kwon,Eun Bo Shim,Young‐Myeong Kim
标识
DOI:10.1016/j.cellsig.2009.01.038
摘要
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.
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