Insulin Stimulates the Clonogenic Potential of Angiogenic Endothelial Progenitor Cells by IGF-1 Receptor-Dependent Signaling
Endothelial progenitor cells (EPCs) have been shown to be involved in vascular regeneration and angiogenesis in experimental diabetes. Because insulin therapy mobilizes circulating progenitor cells, we studied the effects of insulin on outgrowth of EPCs from peripheral blood mononuclear cells of healthy volunteers and patients with type 2 diabetes. Insulin increased the formation of EPC colony-forming units in a dose-dependent manner, half-maximal at 1.5 nM and peaking at 15 nM. Inhibiting the insulin receptor with neutralizing antibodies or antisense oligonucleotides had no effect on EPC outgrowth.1 In contrast, targeting the human insulin-like growth factor 1 (IGF-1) receptor with neutralizing antibodies significantly suppressed insulin-induced outgrowth of EPCs from both healthy controls and patients with type 2 diabetes. This IGF-1 receptor-mediated insulin effect on EPC growth was at least in part dependent on MAP kinases2 and was abrogated when extracellular signal-regulated kinase 1/2 (Erk1/2) and protein kinase 38 (p38) activity was inhibited. To study the functional relevance of the observed insulin effects, we studied EPC-induced tube formation of bovine endothelial cells in vitro. Insulin-stimulated EPCs incorporated into the endothelial tubes and markedly enhanced tube formation. In conclusion, this is the first study showing an insulin-mediated activation of the IGF-1 receptor leading to an increased clonogenic and angiogenic potential of EPCs in vitro.
This study was partly supported by the Deutsche Diabetes Stiftung (PMH), the Manfred Lautenschläger Stiftung (PPN) and the Network Aging Research (NAR) (A.B./P.M.H.). The authors are grateful to Prof. G. Haensch, Institute for Immunology, University of Heidelberg, for support in FACS analysis.
- 13.Peichev M, et al. (2000) Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood 95:952–8.Google Scholar
- 37.Devin JK, et al. (2007) Low-dose growth hormone administration mobilizes endothelial progenitor cells in healthy adults. Growth Horm. IGF Res. Dec 29 [Epub ahead of print].Google Scholar
- 48.Fadini GP, et al. (2007) Maternal insulin therapy increases fetal endothelial progenitor cells during diabetic pregnancy. Diabetes Care Dec 27 [Epub ahead of print].Google Scholar