Abstract 10416: Leptin Promotes the Mobilization of Fetal Liver Kinase 1-Positive Vascular Progenitor Cells From the Bone Marrow in a NOX2 / MMP9-dependent Manner and Enhances Neovascularization after Ischemia.
Experimental evidence suggests that bone marrow-derived progenitor cells participate in the formation of new blood vessels and endothelial repair. We have previously shown that the adipokine leptin enhances the recruitment and incorporation of EPC into neointimal lesions and promotes re-endothelialization after vascular injury. In the present study, we examined the potential of leptin to promote ischemia-induced neovascularization and the contribution of bone marrow-derived progenitor cells to this process. In wildtype (WT) mice, daily injection of leptin (0.6 μg/g) over 5 days significantly promoted new vessel formation after hindlimb ischemia, as determined by quantification of CD31+ capillary endothelial cells (P<0.01). Furthermore, leptin significantly increased the number of spleen-derived acLDL+, lectin+ EPC (P<0.01), and enhanced their potential to integrate into EC networks or sprouts (P<0.001). Analysis of GFP-positive bone marrow chimeric WT mice confirmed the bone marrow origin of integrated CD31+ cells. Moreover, flow cytometry demonstrated that leptin significantly increased the number of circulating (GFP+) sca1+, flk1+ vascular progenitor cells (P<0.05). PCR analysis, flow cytometry and histochemistry confirmed expression of the leptin receptor (ObR) on bone marrow cells. For example, 20±2.5% of the cells were found to express ObR and also were highly positive for the SCF receptor. The effects of leptin on the mobilization of sca1+, flk1+ or on angiogenesis were abolished in mice transplanted with bone marrow from ObR-deficient db/db mice. Regarding potential mechanisms, bone marrow analysis revealved an increased NOX2 and MMP9 (P<0.05 and P<0.01) as well as a decreased TIMP1 (P<0.05) expression, and the effects of leptin on MMP9 and TIMP1 were abolished in db/db, but also in NOX2 deficient mice. Consistently, leptin administration was associated with highly elevated serum SCF levels compared to control mice (P<0.001). Taken together, our study suggest that the proangiogenic effects of leptin may involve its interaction with ObR-positive cells within the bone marrow, activation of specific signal transduction pathways, in particular, NOX2-MMP9-SCF, as well as enhanced mobilization of flk1+ vascular progenitor cells.
- © 2010 by American Heart Association, Inc.