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Cardiovascular Research Advance Access [Accepted Manuscript] published online on December 18, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm111
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VISFATIN INDUCES HUMAN ENDOTHELIAL VEGF AND MMP-2/9 PRODUCTION VIA MAPK AND PI3K/Akt SIGNALLING PATHWAYS: NOVEL INSIGHTS INTO VISFATIN-INDUCED ANGIOGENESIS

Raghu Adya, MBBS, MSc, Bee K Tan, MBBS, Anu Punn, PhD, Jing Chen, PhD and Harpal S Randeva, MBChB, FRCP, MD, PhD

Endocrinology & Metabolism Group, Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK

CORRESPONDENCE: Dr Harpal S Randeva MBCHB, FRCP, MD, PhD Endocrinology & Metabolism Group Clinical Sciences Research Institute Warwick Medical School University of Warwick Coventry CV4 7AL, UK Tel: + 44 2476 572552 Fax: + 44 2476 523701 E-mail: Harpal.Randeva{at}warwick.ac.uk

Aim: 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 VEGF (vascular endothelial growth factor) and matrix metalloproteinases (MMP-2, MMP-9) production and the potential signalling cascades.

Methods & Results: In human umbilical vein endothelial cells (HUVEC), 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 sFlt-1 (soluble FMS-like tyrosine kinase-1)] 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 ERK1/2 (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 ERK1/2 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.

Conclusions: 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.

Time for primary review: 25


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