1. Leptin promotes the mobilization of vascular progenitor cells and neovascularization by NOX2-mediated activation of MMP9.
- Author
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Schroeter MR, Stein S, Heida NM, Leifheit-Nestler M, Cheng IF, Gogiraju R, Christiansen H, Maier LS, Shah AM, Hasenfuss G, Konstantinides S, and Schäfer K
- Subjects
- Animals, Bone Marrow Transplantation, Enzyme Activation, Hematopoietic Stem Cells physiology, Hindlimb blood supply, Ischemia metabolism, Ischemia pathology, Ischemia therapy, Leptin administration & dosage, Leptin physiology, Male, Membrane Glycoproteins deficiency, Membrane Glycoproteins genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, NADPH Oxidase 2, NADPH Oxidases deficiency, NADPH Oxidases genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Reactive Oxygen Species metabolism, Receptors, Leptin deficiency, Receptors, Leptin genetics, Stem Cell Factor blood, Hematopoietic Stem Cells drug effects, Leptin pharmacology, Matrix Metalloproteinase 9 metabolism, Membrane Glycoproteins metabolism, NADPH Oxidases metabolism, Neovascularization, Physiologic drug effects
- Abstract
Aims: Bone marrow (BM) progenitors participate in new vessel formation and endothelial repair. The leptin receptor (ObR) is expressed on hematopoietic cells; however, the effects of leptin on BM progenitor cells and their angiogenic potential are unknown., Methods and Results: In the present study, we show that the short-term administration of leptin (over five consecutive days) into wild-type mice increased the number of circulating, BM-derived sca-1(+), flk-1(+) vascular progenitors, 95 ± 1.7% of which also expressed ObR. Ex vivo stimulation of BM cells with leptin enhanced the expression of NADPH oxidase isoform 2 (NOX2), and the leptin-induced increase in reactive oxygen species production, matrix metalloproteinase-9 (MMP9) expression and circulating soluble KitL levels was absent in mice lacking NOX2. Furthermore, intraperitoneal injections of leptin improved perfusion and increased the number of BM-derived, CD31-positive endothelial cells in ischaemic hindlimbs after femoral artery ligation. The effects of leptin on the mobilization of sca-1(+), flk-1(+) cells and neovascularization were abolished in mice transplanted with BM from ObR-deficient and in NOX2(-/-) mice., Conclusion: Our findings suggest that the angiogenic effects of leptin involve sca-1(+), flk-1(+) vascular progenitor cells mobilized from the BM in response to ObR-mediated activation of NOX2, increased MMP9 expression, and sKitL release.
- Published
- 2012
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