Impairment in ischemia-induced neovascularization in diabetes: bone marrow mononuclear cell dysfunction and therapeutic potential of placenta growth factor treatment.
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.
Tamarat
Radia
R
INSERM U541, Hôpital Lariboisière, IFR Circulation-Paris 7, Université Paris 7, Paris, France.
Silvestre
Jean-Sébastien
JS
Le Ricousse-Roussanne
Sophie
S
Barateau
Véronique
V
Lecomte-Raclet
Laurence
L
Clergue
Michel
M
Duriez
Micheline
M
Tobelem
Gérard
G
Lévy
Bernard I
BI
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*
C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor