Endocrine Abstracts

Objectives: Visfatin and monocyte-chemoattractant-protein-1 (MCP-1) are elevated in cardiovascular pathologies, insulin-resistant and dysmetabolic states. Visfatin has been reported to exhibit pro-angiogenic actions in human endothelial cells by the induction of endothelial gelatinases and VEGF. Given MCP-1’s well described pro-angiogenic properties we sought to study the potential interaction between visfatin, MCP-1 and VEGF in human endothelial cells. More importantly, we explored the possible autocrine/paracine mechanisms governing this potential interaction and the effect of visfatin on MCP-1’s putative receptor (CCR2 receptor) in human endothelial cells.

Methods and results: Using in vitro angiogenic assays (capillary tube formation and migration), western-blotting and RT-PCR, we found that visfatin, dose-dependently, induced MCP-1 as well as CCR2 levels. We also studied the involvement of PI3Kinase, MAPKinase and NF-κB pathways in visfatin induced MCP-1/CCR2 levels by employing LY294002, U0126 and BAY11-7085, respectively. We found the increase in MCP-1 and CCR2 levels by visfatin were negated by LY294002 and BAY11-7085, but not with U0126, suggesting the crucial role of PI3Kinase and NF-κB pathways in visfatin induced MCP-1 and its autocrine regulation via the CCR2 receptor. We consolidate the role of MCP-1 in visfatin-induced angiogenesis by employing CCR2 antagonist (RS- 102895) and MCP-1 neutralizing antibody, respectively. Furthermore, MCP-1 blockade by employing the neutralising antibody, decreased visfatin induced VEGF production, suggesting that visfatin induced MCP-1 production leads to endothelial angiogenesis via VEGF.

Conclusions: Our novel data reveal that MCP-1 is pivotal in modulating visfatin induced angiogenesis via NF-κB and PI3Kinase pathways. Furthermore, our findings elucidate the potential influence of autocrine/paracrine mechanisms (via the CCR2 receptor) underlying visfatin’s angiogenic effects through MCP-1.