Leptin enhances the potency of circulating angiogenic cells via src kinase and integrin (alpha)vbeta5: 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).


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 alphavbeta5 integrins, which depended on the interaction of leptin with its receptor ObR, and on Janus kinase (JAK) 2- and phospholipase C (PLC) gamma-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) normalized protein tyrosine phosphatase 1B expression in CACs and restored their responsiveness to leptin. A similar dose-dependent response was found after incubation of CACs from obese subjects with a protein tyrosine phosphatase 1B inhibitor ex vivo.


CONCLUSIONS
Our results point to the ObR-Src kinase-alphavbeta5 cross talk as a distinct novel component of the network of specific interactions between integrins and cytokine receptors in angiogenesis.
Heida
Nana-Maria
NM
Department of Cardiology and Pulmonology, Georg August University, Goettingen, Germany.
Leifheit-Nestler
Maren
M
Schroeter
Marco R
MR
Müller
Jan-Peter
JP
Cheng
I-Fen
IF
Henkel
Sarah
S
Limbourg
Anne
A
Limbourg
Florian P
FP
Alves
Frauke
F
Quigley
James P
JP
Ruggeri
Zaverio M
ZM
Hasenfuss
Gerd
G
Konstantinides
Stavros
S
Schäfer
Katrin
K
D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D016022:Case-Control Studies; D002448:Cell Adhesion; D002465:Cell Movement; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology; D004789:Enzyme Activation; D006614:Hindlimb; D006801:Humans; D007511:Ischemia / Q000201:enzymology / Q000503:physiopathology / Q000601:surgery; D053614:Janus Kinase 2 / Q000378:metabolism; D020738:Leptin / Q000097:blood / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000201:enzymology* / Q000276:immunology / Q000637:transplantation; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018482:Muscle, Skeletal / Q000098:blood supply; D018919:Neovascularization, Physiologic; D009765:Obesity / Q000097:blood / Q000503:physiopathology / Q000628:therapy; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D054411:Receptors, Leptin / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular; D014162:Transfection; D015854:Up-Regulation; D015431:Weight Loss; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D018952:Antigens, CD34; D020738:Leptin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D054411:Receptors, Leptin; D019030:Receptors, Vitronectin; D011994:Recombinant Proteins; C064660:integrin alphaVbeta5; D053614:Janus Kinase 2; D019061:src-Family Kinases; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D051966:Phospholipase C gamma