Visfatin induces human endothelial VEGF and MMP-2/9 production via MAPK and PI3K/Akt signalling pathways: Novel insights into visfatin-induced angiogenesis

Endocrinology and Metabolism Group, Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK.
Cardiovascular Research (Impact Factor: 5.94). 06/2008; 78(2):356-65. DOI: 10.1093/cvr/cvm111
Source: PubMed


Visfatin is a novel adipokine whose plasma concentrations are altered in obesity and obesity-related disorders; these states are associated with an increased incidence of cardiovascular disease. We therefore investigated the effect of visfatin on vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP-2, MMP-9) production and the potential signalling cascades.
In human umbilical vein endothelial cells (HUVECs), visfatin significantly and dose-dependently up-regulated gene expression and protein production of VEGF and MMPs and down-regulated expression of tissue inhibitors of MMPs (TIMP-1 and TIMP-2). The gelatinolytic activity of MMPs (analysed by zymography) correlated with mRNA and western blot findings. Interestingly, visfatin significantly up-regulated VEGF receptor 2 expression. Inhibition of VEGFR2 and VEGF [by soluble FMS-like tyrosine kinase-1 (sFlt1)] down-regulated visfatin-induced MMP induction. Visfatin induced dose- and time-dependent proliferation and capillary-like tube formation. Importantly, visfatin was noted to have anti-apoptotic effects. In HUVECs, visfatin dose-dependently activated PI3K/Akt (phosphatidylinositol 3-kinase/Akt) and ERK(1/2) (extracellular signal-regulated kinase) pathways. The functional effects and MMP/VEGF induction were shown to be dependent on the MAPK/PI3K-Akt/VEGF signalling pathways. Inhibition of PI3K/Akt and ERK(1/2) pathways led to significant decrease of visfatin-induced MMP and VEGF production and activation, along with significant reduction in endothelial proliferation and capillary tube formation.
Our data provide the first evidence of visfatin-induced endothelial VEGF and MMP production and activity. Further, we show for the first time the involvement of the MAPK and PI3K/Akt signalling pathways in mediating these actions, as well as endothelial cell proliferation. Collectively, our findings provide novel insights into visfatin-induced endothelial angiogenesis.

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    • "Also circulating monocytes and macrophages, seem to be responsible for resistin production in humans [18]. Visfatin is a novel adipokine, released from VAT and perivascular adipose tissue, which has an insulinmimetic effect [17] [19]. Visfatin has multiple functions in the vasculature: it stimulates growth of vascular smooth muscle cells and endothelial angiogenesis and it can also directly affect vascular contractility. "
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    • "Moreover, it has been found that visfatin leads to phosphorylation of insulin receptor, insulin receptor substrate-1 (IRS-1) and -2 (IRS-2), phosphatidylinositol-3-OH kinase (PI3K), cellular Akt/ protein kinase B (Akt) and exerts its antiapoptotic effect through activation of mitogen-activated protein kinase (MAPK) (Adya et al., 2007; Rongvaux et al., 2002) . "
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