Visfatin exerts angiogenic effects on human umbilical vein endothelial cells through the mTOR signaling pathway

Abstract

The biologically active factors known as adipocytokines are secreted primarily by adipose tissues and can act as modulators of angiogenesis. Visfatin, an adipocytokine that has recently been reported to have angiogenic properties, is upregulated in diabetes, cancer, and inflammatory diseases. Because maintenance of an angiogenic balance is critically important in the management of these diseases, understanding the molecular mechanism by which visfatin promotes angiogenesis is very important. In this report, we describe our findings demonstrating that visfatin stimulates the mammalian target of the rapamycin (mTOR) pathway, which plays important roles in angiogenesis. Visfatin induced the expression of hypoxia-inducible factor 1α (HIF1α) and vascular endothelial growth factor (VEGF) in human endothelial cells. Inhibition of the mTOR pathway by rapamycin eliminated the angiogenic and proliferative effects of visfatin. The visfatin-induced increase in VEGF expression was also eliminated by RNA interference-mediated knockdown of the 70-kDa ribosomal protein S6 kinase (p70S6K), a downstream target of mTOR. Visfatin inactivated glycogen synthase kinase 3β (GSK3β) by phosphorylating it at Ser-9, leading to the nuclear translocation of β-catenin. Both rapamycin co-treatment and p70S6K knockdown inhibited visfatin-induced GSK3β phosphorylation at Ser-9 and nuclear translocation of β-catenin. Taken together, these results indicate that mTOR signaling is involved in visfatin-induced angiogenesis, and that this signaling leads to visfatin-induced VEGF expression and nuclear translocation of β-catenin. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.

The experimental renal cell carcinoma model in the chick embryo

“…synthesis and controls cell survival and inflammation [50,51]. Exogenous PBEF1/NAMPT/Visfatin has proangiogenic activity, regulates endothelial IL6 production through Stat3 in vitro [52] and can induce the mTOR pathway in HUVEC cells [53]. PBEF1 is upregulated at the mRNA level in various tumor types such as prostate cancers [54] and correlated with poor survival in breast cancer [55].…”

Selective inactivation of NADPH oxidase 2 causes regression of vascularization and the size and stability of atherosclerotic plaques

“…In particular, they showed that visfatin induces VEGF and VEGFR2 and enhanced VEGF signaling results in increased expression of MMP-2 and MMP-9 [25]. Visfatin plays important roles in angiogenesis, and was also shown to induce the expression of HIF1α and MMP production and activity [38,39]. This adipokine should be regarded as an inflammatory mediator, localized to foam cell macrophages within unstable atherosclerotic lesions, that potentially plays a role in plaque destabilization [40].…”

NAMPT and NAMPT-controlled NAD Metabolism in Vascular Repair

“…Inhibition of the mTOR pathway by rapamycin eliminated the angiogenic and proliferative effects of extracellular NAMPT. 68 Moreover, extracellular NAMPT was found to upregulate and stabilize mRNA of endothelial nitric oxide synthase (eNOS) by activating Akt and MAP kinases signaling pathways, which in turn enhances proliferation, migration, and tube formation in HUVECs. 59 According to these studies in endothelial cells, it seems that various signaling transduction pathways can be activated by extracellular NAMPT; however, how extracellular NAMPT exerts these diverse cytokine-like effects is still unknown.…”