Leptin enhances the recruitment of endothelial progenitor cells into neointimal lesions after vascular injury by promoting integrin-mediated adhesion.
The adipocytokine leptin modulates vascular remodeling and neointima formation. Because endothelial progenitor cells (EPCs) participate in vascular repair, we analyzed the effects of leptin on human EPC function in vitro and in vivo. After 7 days in culture, EPCs expressed the leptin receptor and responded to leptin stimulation with increased STAT3 phosphorylation. Incubation of EPCs with leptin (at concentrations between 1 and 100 ng/mL) increased the number of EPCs adhering to vitronectin and fibronectin in a receptor-specific manner. It also enhanced the capacity of EPCs to incorporate into a monolayer of human endothelial cells and the adherence of these cells to activated platelets. Leptin upregulated alphavbeta5 and alpha4 integrin expression in EPCs, and the effects of leptin on EPC function could be prevented, at least in part, by RGD peptides and function-blocking antibodies. Intravenous injection of fluorescently labeled human EPCs into athymic nude mice shortly after vascular injury revealed that preincubation of EPCs with leptin augmented their accumulation within intimal lesions, accelerating reendothelialization and decreasing neointima formation in an alphavbeta5 and alpha4 integrin-dependent manner. Our findings suggest that leptin specifically modulates the adhesive properties and the homing potential of EPCs and may thus enhance their capacity to promote vascular regeneration in vivo.
Schroeter
Marco R
MR
Department of Cardiology and Pulmonary Medicine, University of Goettingen, Robert Koch Strasse 40, D-37099 Goettingen, Germany.
Leifheit
Maren
M
Sudholt
Philipp
P
Heida
Nana-Maria
NM
Dellas
Claudia
C
Rohm
Ilonka
I
Alves
Frauke
F
Zientkowska
Marta
M
Rafail
Stavros
S
Puls
Miriam
M
Hasenfuss
Gerd
G
Konstantinides
Stavros
S
Schäfer
Katrin
K
D002448:Cell Adhesion / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D039441:Integrin alpha4 / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017539:Tunica Intima / Q000166:cytology / Q000378:metabolism
D020738:Leptin; D009842:Oligopeptides; D012333:RNA, Messenger; D054411:Receptors, Leptin; D019030:Receptors, Vitronectin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C064660:integrin alphaVbeta5; D039441:Integrin alpha4; C047981:arginyl-glycyl-aspartic acid