Erythropoietin induces excessive neointima formation: a study in a rat carotid artery model of vascular injury.
A therapeutic strategy that would mitigate the events leading to hyperplasia and facilitate re-endothelialization of an injured artery after balloon angioplasty could be effective for a long-term patency of the artery. It is hypothesized that erythropoietin (EPO), which has both anti-inflammatory and antiapoptotic properties, will prevent hyperplasia, and its ability to proliferate and mobilize endothelial progenitor cells will re-endothelialize the injured artery. To test this hypothesis, EPO (5000 IU/kg) in solution was injected intraperitoneally 6 hours before vascular injury and then on every alternate day for a week or as a single dose (5000 IU/kg) in a sustained release gel formulation 1 week before the vascular injury. Morphometric analysis revealed nearly continuous re-endothelialization of the injured artery in EPO solution-treated animals (90% vs less than 20% in saline control); however, the treatment also caused excessive neointima formation (intima/media ratio, 2.10 +/- 0.09 vs 1.60 +/- 0.02 saline control, n = 5, P < .001). The EPO gel also induced similar excessive neointima formation. Immunohistochemical analysis of the injured arteries from the animals treated with EPO solution demonstrated a significant angiogenic response in adventitia and media, thus explaining the formation of excessive neointima. Although the results are in contrast to expectation, they explain a greater degree of stenosis seen in hemodialysis access fistulas in patients who are on EPO therapy for anemic condition. The results also caution the use of EPO, particularly in patients who are at a risk of vascular injury or are suffering from an atherosclerotic condition.
Reddy
Maram K
MK
Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Vasir
Jaspreet K
JK
Hegde
Ganapati V
GV
Joshi
Shantaram S
SS
Labhasetwar
Vinod
V
D000818:Animals; D002339:Carotid Arteries / Q000473:pathology; D020212:Carotid Artery Injuries / Q000188:drug therapy*; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D004921:Erythropoietin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D005782:Gels; D006965:Hyperplasia / Q000139:chemically induced; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D009389:Neovascularization, Pathologic / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
D003692:Delayed-Action Preparations; D005782:Gels; D004921:Erythropoietin