title: Impairment in ischemia-induced neovascularization in diabetes: bone marrow mononuclear cell dysfunction and therapeutic potential of placenta growth factor treatment.
abstract: Mechanisms that hinder ischemia-induced neovascularization in diabetes remain poorly understood. We hypothesized that endogenous bone marrow mononuclear cell (BM-MNC) dysfunction may contribute to the abrogated postischemic revascularization reaction associated with diabetes. We first analyzed the effect of diabetes (streptozotocin, 40 mg/kg) on BM-MNC pro-angiogenic potential in a model of surgically induced hindlimb ischemia. In nondiabetic animals, transplantation of BM-MNCs isolated from nondiabetic animals raised the ischemic/nonischemic angiographic score, capillary number, and blood flow recovery by 1.8-, 2.7-, and 2.2-fold, respectively, over that of PBS-injected nondiabetic animals (P < 0.05). Administration of diabetic BM-MNCs also improved the neovascularization reaction in ischemic hindlimbs of nondiabetic mice but to a lesser extent from that observed with nondiabetic BM-MNC transplantation. In diabetic mice, injection of nondiabetic BM-MNCs was still more efficient than that of diabetic BM-MNCs. Such BM-MNC dysfunction was associated with the impairment of diabetic BM-MNC capacity to differentiate into endothelial progenitor cells (EPCs) in vitro and to participate in vascular-like structure formation in a subcutaneous Matrigel plug. Placenta growth factor (PlGF) administration improved by sixfold the number of EPCs differentiated from diabetic BM-MNCs in vitro and enhanced ischemic/nonischemic angiographic score, capillary number and blood flow recovery by 1.9-, 1.5- and 1.6-fold, respectively, over that of untreated diabetic animals (P < 0.01). Endogenous BM-MNC pro-angiogenic potential was affected in diabetes. Therapeutic strategy based on PlGF administration restored such defects and improved postischemic neovascularization in diabetic mice.
authors.affiliation: INSERM U541, Hôpital Lariboisière, IFR Circulation-Paris 7, Université Paris 7, Paris, France.
authors.forename: Radia
authors.initials: R
authors.lastname: Tamarat
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Silvestre
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Ricousse-Roussanne
authors.forename: Véronique
authors.initials: V
authors.lastname: Barateau
authors.forename: Laurence
authors.initials: L
authors.lastname: Lecomte-Raclet
authors.forename: Michel
authors.initials: M
authors.lastname: Clergue
authors.forename: Micheline
authors.initials: M
authors.lastname: Duriez
authors.forename: Gérard
authors.initials: G
authors.lastname: Tobelem
authors.forename: Bernard I
authors.initials: BI
authors.lastname: Lévy
mesh_terms: D000792:Angiography; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D006614:Hindlimb / Q000098:blood supply / Q000473:pathology / Q000601:surgery; D007511:Ischemia / Q000188:drug therapy / Q000473:pathology* / Q000601:surgery; D017078:Laser-Doppler Flowmetry; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000473:pathology; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000494:pharmacology*
chemical_list: C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor