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Nitric Oxide Cytoskeletal–Induced Alterations Reverse the Endothelial Progenitor Cell Migratory Defect Associated With Diabetes

¹ Division of Nephrology, Hypertension, and Transplantation, University of Florida, Gainesville, Florida
² Division of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida
³ Department of Biomedical Engineering, University of Florida, Gainesville, Florida
⁴ Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, Florida

Address correspondence and reprint requests to Dr. Mark S. Segal, University of Florida, Division of Nephrology, Hypertension,Transplantation, P.O. Box 100224, Gainesville, FL 32610-0267. E-mail: segalms{at}medicine.ufl.edu. Or Dr. Maria B. Grant, University of Florida, Division of PharmacologyTherapeutics, P.O. Box 100267, Gainesville, FL 32610-0267. E-mail: grantma{at}pharmacology.ufl.edu

Abbreviations: CKD, chronic kidney disease; DETA/NO, diethylenetriaamine NONOate; EPC, endothelial progenitor cell; FITC, fluorescein isothiocyanate; HREC, human retinal endothelial cell; SDF-1, stromal-derived factor-1; VASP, vasodilator-stimulated phosphoprotein; VEGF, vascular endothelial growth factor

Stromal-derived factor-1 (SDF-1) is a critical chemokine for endothelial progenitor cell (EPC) recruitment to areas of ischemia, allowing these cells to participate in compensatory angiogenesis. The SDF-1 receptor, CXCR4, is expressed in developing blood vessels as well as on CD34+ EPCs. We describe that picomolar and nanomolar concentrations of SDF-1 differentially influence neovascularization, inducing CD34+ cell migration and EPC tube formation. CD34+ cells isolated from diabetic patients demonstrate a marked defect in migration to SDF-1. This defect is associated, in some but not all patients, with a cell surface activity of CD26/dipeptidyl peptidase IV, an enzyme that inactivates SDF-1. Diabetic CD34+ cells also do not migrate in response to vascular endothelial growth factor and are structurally rigid. However, incubating CD34+ cells with a nitric oxide (NO) donor corrects this migration defect and corrects the cell deformability. In addition, exogenous NO alters vasodilator-stimulated phosphoprotein and mammalian-enabled distribution in EPCs. These data support a common downstream cytoskeletal alteration in diabetic CD34+ cells that is independent of growth factor receptor activation and is correctable with exogenous NO. This inability of diabetic EPCs to respond to SDF-1 may contribute to aberrant tissue vascularization and endothelial repair in diabetic patients.

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