This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ebrahimian, T. G Articles by Silvestre, J.-S. Search for Related Content PubMed PubMed Citation Articles by Ebrahimian, T. G Articles by Silvestre, J.-S.

(American Journal of Pathology. 2006;169:719-728.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060042

NADPH Oxidase-Derived Overproduction of Reactive Oxygen Species Impairs Postischemic Neovascularization in Mice with Type 1 Diabetes

Téni G Ebrahimian^*, Christophe Heymes, Dong You^*, Olivier Blanc-Brude^*, Barend Mees, Ludovic Waeckel^*, Micheline Duriez^*, José Vilar^*, Ralph P. Brandes, Bernard I. Levy^*, Ajay M. Shah and Jean-Sébastien Silvestre^*

From the Cardiovascular Research Center,^* INSERM Lariboisière U689, Université Paris, Paris, France; the Cardiovascular Division, King’s College, London, United Kingdom; the Departments of Vascular Surgery and Cell Biology and Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands; and the Institut fur Kardiovaskulare Physiologie, Universitat Frankfurt, Frankfurt, Germany

We hypothesized that diabetes-induced oxidative stress may affect postischemic neovascularization. The response to unilateral femoral artery ligation was studied in wild-type or gp91^phox-deficient control or type 1 diabetic mice or in animals treated with the anti-oxidant N-acetyl-L-cysteine (NAC) or with in vivo electrotransfer of a plasmid encoding dominant-negative Rac1 (50 µg) for 21 days. Postischemic neovascularization was reduced in diabetic mice in association with down-regulated vascular endothelial growth factor-A protein levels. In diabetic animals vascular endothelial growth factor levels and postischemic neovascularization were restored to nondiabetic levels by the scavenging of reactive oxygen species (ROS) by NAC administration or the inhibition of ROS generation by gp91^phox deficiency or by administration of dominant-negative Rac1. Finally, diabetes reduced the ability of adherent bone marrow-derived mononuclear cells (BM-MNCs) to differentiate into endothelial progenitor cells. Treatment with NAC (3 mmol/L), apocynin (200 µmol/L), or the p38MAPK inhibitor LY333351 (10 µmol/L) up-regulated the number of endothelial progenitor cell colonies derived from diabetic BM-MNCs by 1.5-, 1.6-, and 1.5-fold, respectively (P < 0.05). In the ischemic hindlimb model, injection of diabetic BM-MNCs isolated from NAC-treated or gp91^phox-deficient diabetic mice increased neovascularization by 1.5-fold greater than untreated diabetic BM-MNCs (P < 0.05). Thus, inhibition of NADPH oxidase-derived ROS overproduction improves the angiogenic and vasculogenic processes and restores postischemic neovascularization in type 1 diabetic mice.

This article has been cited by other articles:

				P. Foubert, G. Matrone, B. Souttou, C. Lere-Dean, V. Barateau, J. Plouet, S. Le Ricousse-Roussanne, B. I. Levy, J.-S. Silvestre, and G. Tobelem Coadministration of Endothelial and Smooth Muscle Progenitor Cells Enhances the Efficiency of Proangiogenic Cell-Based Therapy Circ. Res., September 26, 2008; 103(7): 751 - 760. [Abstract] [Full Text] [PDF]

				L. Xie, X. Zhu, Y. Hu, T. Li, Y. Gao, Y. Shi, and S. Tang Mitochondrial DNA Oxidative Damage Triggering Mitochondrial Dysfunction and Apoptosis in High Glucose-Induced HRECs Invest. Ophthalmol. Vis. Sci., September 1, 2008; 49(9): 4203 - 4209. [Abstract] [Full Text] [PDF]

				D. You, C. Cochain, C. Loinard, J. Vilar, B. Mees, M. Duriez, B. I. Levy, and J.-S. Silvestre Combination of the Angiotensin-Converting Enzyme Inhibitor Perindopril and the Diuretic Indapamide Activate Postnatal Vasculogenesis in Spontaneously Hypertensive Rats J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 766 - 773. [Abstract] [Full Text] [PDF]

				D. You, C. Cochain, C. Loinard, J. Vilar, B. Mees, M. Duriez, B. I. Levy, and J.-S. Silvestre Hypertension Impairs Postnatal Vasculogenesis: Role of Antihypertensive Agents Hypertension, June 1, 2008; 51(6): 1537 - 1544. [Abstract] [Full Text] [PDF]

				J.-S. Silvestre, Z. Mallat, A. Tedgui, and B. I. Levy Post-ischaemic neovascularization and inflammation Cardiovasc Res, May 1, 2008; 78(2): 242 - 249. [Abstract] [Full Text] [PDF]

				P. Dentelli, A. Rosso, A. Zeoli, R. Gambino, L. Pegoraro, G. Pagano, R. Falcioni, and M. F. Brizzi Oxidative Stress-mediated Mesangial Cell Proliferation Requires RAC-1/Reactive Oxygen Species Production and beta4 Integrin Expression J. Biol. Chem., September 7, 2007; 282(36): 26101 - 26110. [Abstract] [Full Text] [PDF]

				H. W. Kim, A. Lin, R. E. Guldberg, M. Ushio-Fukai, and T. Fukai Essential Role of Extracellular SOD in Reparative Neovascularization Induced by Hindlimb Ischemia Circ. Res., August 17, 2007; 101(4): 409 - 419. [Abstract] [Full Text] [PDF]

				S. A. Sorrentino, F. H. Bahlmann, C. Besler, M. Muller, S. Schulz, N. Kirchhoff, C. Doerries, T. Horvath, A. Limbourg, F. Limbourg, et al. Oxidant Stress Impairs In Vivo Reendothelialization Capacity of Endothelial Progenitor Cells From Patients With Type 2 Diabetes Mellitus: Restoration by the Peroxisome Proliferator-Activated Receptor-{gamma} Agonist Rosiglitazone Circulation, July 10, 2007; 116(2): 163 - 173. [Abstract] [Full Text] [PDF]

				G. P. Fadini, S. Sartore, C. Agostini, and A. Avogaro Significance of Endothelial Progenitor Cells in Subjects With Diabetes Diabetes Care, May 1, 2007; 30(5): 1305 - 1313. [Full Text] [PDF]