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PSGL-1-mediated activation of EphB4 increases the proangiogenic potential of endothelial progenitor cells.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2007 Jun; Vol. 117 (6), pp. 1527-37. Date of Electronic Publication: 2007 May 17. - Publication Year :
- 2007
-
Abstract
- Endothelial progenitor cell (EPC) transplantation has beneficial effects for therapeutic neovascularization; however, only a small proportion of injected cells home to the lesion and incorporate into the neocapillaries. Consequently, this type of cell therapy requires substantial improvement to be of clinical value. Erythropoietin-producing human hepatocellular carcinoma (Eph) receptors and their ephrin ligands are key regulators of vascular development. We postulated that activation of the EphB4/ephrin-B2 system may enhance EPC proangiogenic potential. In this report, we demonstrate in a nude mouse model of hind limb ischemia that EphB4 activation with an ephrin-B2-Fc chimeric protein increases the angiogenic potential of human EPCs. This effect was abolished by EphB4 siRNA, confirming that it is mediated by EphB4. EphB4 activation enhanced P selectin glycoprotein ligand-1 (PSGL-1) expression and EPC adhesion. Inhibition of PSGL-1 by siRNA reversed the proangiogenic and adhesive effects of EphB4 activation. Moreover, neutralizing antibodies to E selectin and P selectin blocked ephrin-B2-Fc-stimulated EPC adhesion properties. Thus, activation of EphB4 enhances EPC proangiogenic capacity through induction of PSGL-1 expression and adhesion to E selectin and P selectin. Therefore, activation of EphB4 is an innovative and potentially valuable therapeutic strategy for improving the recruitment of EPCs to sites of neovascularization and thereby the efficiency of cell-based proangiogenic therapy.
- Subjects :
- Animals
Base Sequence
Cell Adhesion
Cells, Cultured
DNA Primers genetics
E-Selectin metabolism
Endothelial Cells cytology
Endothelial Cells drug effects
Ephrin-B2 metabolism
Ephrin-B2 pharmacology
Fetal Blood cytology
Fetal Stem Cells cytology
Fetal Stem Cells drug effects
Hindlimb blood supply
Humans
In Vitro Techniques
Ischemia metabolism
Ischemia pathology
Ischemia therapy
Male
Membrane Glycoproteins antagonists & inhibitors
Membrane Glycoproteins genetics
Mice
Mice, Nude
P-Selectin metabolism
RNA Interference
RNA, Small Interfering genetics
Receptor, EphB4 antagonists & inhibitors
Receptor, EphB4 genetics
Endothelial Cells metabolism
Fetal Stem Cells metabolism
Membrane Glycoproteins metabolism
Neovascularization, Physiologic drug effects
Receptor, EphB4 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9738
- Volume :
- 117
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 17510705
- Full Text :
- https://doi.org/10.1172/JCI28338