Abstract
BackgroundTransplantation of vasculogenic progenitor cells (VPC) improves neovascularization after ischemia. However, patients with type 2 diabetes mellitus show a reduced VPC number and impaired functional activity. Previously, we demonstrated that p38 kinase inhibition prevents the negative effects of glucose on VPC number by increasing proliferation and differentiation towards the endothelial lineage in vitro. Moreover, the functional capacity of progenitor cells is reduced in a mouse model of metabolic syndrome including type 2 diabetes (Leprdb) in vivo.FindingsThe aim of this study was to elucidate the underlying signalling mechanisms in vitro and in vivo. Therefore, we performed DNA-protein binding arrays in the bone marrow of mice with metabolic syndrome, in blood-derived progenitor cells of diabetic patients as well as in VPC ex vivo treated with high levels of glucose. The transcriptional activation of ETS transcription factors was increased in all samples analyzed. Downregulation of ETS1 expression by siRNA abrogated the reduction of VPC number induced by high-glucose treatment. In addition, we observed a concomitant suppression of the non-endothelial ETS-target genes matrix metalloproteinase 9 (MMP9) and CD115 upon short term lentiviral delivery of ETS-specific shRNAs. Long term inhibition of ETS expression by lentiviral infection increased the number of cells with the endothelial markers CD144 and CD105.ConclusionThese data demonstrate that diabetes leads to dysregulated activation of ETS, which blocks the functional activity of progenitor cells and their commitment towards the endothelial cell lineage.
Highlights
Postnatal vessel formation, known as angiogenesis, was attributed to the migration and proliferation of preexisting mature endothelial cells [1,2]
These data demonstrate that diabetes leads to dysregulated activation of ETS, which blocks the functional activity of progenitor cells and their commitment towards the endothelial cell lineage
Because diabetes leads to impairment in number and functional activity of progenitor cells in patients [7,8,16], we wanted to elucidate the potential underlying signalling mechanisms
Summary
Postnatal vessel formation, known as angiogenesis, was attributed to the migration and proliferation of preexisting mature endothelial cells [1,2]. In vivo and in vitro studies revealed that endothelial progenitor cells from patients with type 1 and type 2 diabetes were impaired in number and function [5,6,7,8]. Marchetti et al demonstrated that high glucose levels (33 mM) increased apoptosis of endothelial progenitor cells in vitro and impaired the PI3-kinase/Akt pathway [9]. No animal studies in models for type 2 diabetes or metabolic syndrome were conducted to identify signalling mechanisms in vivo which contribute to high glucose-induced impairment of progenitor cells. The functional capacity of progenitor cells is reduced in a mouse model of metabolic syndrome including type 2 diabetes (Leprdb) in vivo
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