Leptin Enhances the Potency of Circulating Angiogenic Cells Via Src Kinase and Integrin αvβ5: Implications for Angiogenesis in Human Obesity

Objective— To investigate the capacity of the adipokine leptin to promote angiogenesis by modulating the function of circulating angiogenic cells (CACs). Methods and Results— In vitro, leptin specifically promoted CAC adhesion to tubular endothelial structures and migration along outgrowing sprouts of endothelial cells. In vivo, stimulation of CACs with leptin increased their capacity to promote new vessel formation in the chorioallantoic membrane of chicken embryos and to improve neovascularization of ischemic murine hind limbs. These effects required the phosphorylation of αvβ5 integrins, which depended on the interaction of leptin with its receptor ObR, and on Janus kinase (JAK) 2– and phospholipase C (PLC) γ-mediated activation of Src kinase. Protein tyrosine phosphatase 1B, a negative regulator of leptin signaling, was overexpressed in CACs from obese, hyperleptinemic individuals, and this was associated with insensitivity of CACs to the angiogenic effects of leptin. Weight loss (by 30±15 kg) normali...