Induction of angiogenesis by murine resistin: Putative role of PI3-kinase and NO-dependent pathways

Adipose tissue is a highly active endocrine organ, secreting bioactive molecules, adipokines, into the circulation. Obesity results in dysregulated adipokine secretion, contributing to pathophysiologies associated with this disorder, including insulin resistance and cardiovascular disease. Objectives: To establish whether resistin, a novel bioactive molecule produced by murine adipose tissue, and implicated in insulin resistance in rodents, can induce angiogenic responses in aortic tissues and endothelial cells in vitro, and to investigate the signal transduction pathways involved in these responses. Results: Recombinant murine resistin (5-100 ng ml(-1)) induced sprouting of cellular networks and migration from murine aortic arch explants, primary aortic endothelial cells and in a 'wound healing' model utilising murine b.End5 endothelioma cells. The increased migration and sprouting of endothelial cells, due to resistin, were blocked by wortmannin (100 nM) and LY294002 (10 mu M), inhibitors of phosphatidylinositol-3-kinase (PI3K), and accompanied by PI3K-dependent phosphorylation of Akt; moreover, while the changes were not associated with altered production of nitric oxide (NO), resistin-induced angiogenic responses were inhibited by IKK Inhibitor X (5 mu M), an inhibitor of activation of nuclear factor (NF)-kappa B. Conclusions: Murine resistin induces endothelial cell migration and sprouting of cellular networks via a mechanism which appears dependent upon PI3K and NF-kappa B activity, but independent of altered NO production. Resistin may contribute to angiogenic responses sustaining adipose tissue expansion, or in arterial tissues distal to this site. (C) 2008 Elsevier B.V. All rights reserved.