A systemic combination therapy with granulocyte-colony stimulating factor plus erythropoietin aggravates the healing process of balloon-injured rat carotid arteries.
OBJECTIVE
Percutaneous vascular interventions lead inevitably to a destruction of the endothelial lining at the site of injury. There are conflicting data on the therapeutic benefit of hematopoietic growth factors aiming at mobilisation of circulating endothelial cells to accelerate the reendothelialisation process. Aim of our study was to evaluate the impact of a maximised 7 day-combination therapy with G-CSF plus EPO on the healing process following balloon injury of the rat carotid artery.


RESULTS
Osmotic pumps to systemically deliver G-CSF and EPO at saturating doses during the first seven days post injury were implanted into the peritoneal cavity of splenectomised male Sprague-Dawley rats. Cytokine treatment resulted in significantly elevated numbers of white blood cells, hematocrit levels, circulating hematopoietic stem cells, and-temporarily-circulating endothelial precursors. Functional reendothelialisation as assessed by Evan's blue staining on day 14 post injury was not affected by the cytokine treatment. The neointimal response was analysed on day 7 and 28 post injury, and was significantly higher at the day 7 timepoint (Cytokines: I/M-ratio 1.10+/-0.09 vs. Saline: 0.36+/-0.06). Cytokine treated rats also displayed higher rates of thrombotic occlusion (Cytokines: 25-33% vs. Saline: 0%). Serum levels of PAI-1, TGFbeta1, and PDGF-BB were not elevated in the cytokine treated rats. The proliferative rates both in the injured vessel wall and the surrounding adventitia as assessed by BrdU incorporation were significantly higher in the cytokine treated animals. The number of CD45(pos) hematopoietic cells was significantly higher in the adventitia of the cytokine treated rats. Vasa vasorum were not found to be significantly different. The increased neointimal response was not due to expression of G-CSF- or EPO-receptors on VSMCs within the vessel wall or myofibroblasts in the adventitia.


CONCLUSIONS
The systemic administration of G-CSF plus EPO during the first week after balloon-injury impairs the vascular healing process by increasing the neointimal response and the risk for thrombotic occlusion.
Department of Internal Medicine II, Regensburg University Medical Center, 93053, Regensburg, Germany.
Michael
M
Hack
Frank G
FG
Mascha
Bertram J
BJ
Jobst
Guenter A J
GA
Riegger
Daniel P
DP
Griese
D000818:Animals; D000077214:Becaplermin; D020212:Carotid Artery Injuries / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D002404:Catheterization / Q000009:adverse effects / Q000379:methods; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004921:Erythropoietin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods; D006965:Hyperplasia; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000097:blood; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013927:Thrombosis / Q000139:chemically induced; D053773:Transforming Growth Factor beta1 / Q000097:blood; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects*
D017395:Plasminogen Activator Inhibitor 1; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D053773:Transforming Growth Factor beta1; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D000077214:Becaplermin; D017493:Leukocyte Common Antigens