Transfection of HGF gene enhances endothelial progenitor cell (EPC) function and improves EPC transplant efficiency for balloon-induced arterial injury in hypercholesterolemic rats.
Risk factors for coronary heart disease can reduce the number of endothelial progenitor cells (EPCs) and impair EPC function, thus hindering their utility in the treatment of cardiovascular diseases. In the present study, we began exploring the feasibility of genetic modification of EPCs with hepatocyte growth factor (HGF) to counter the effects of these risk factors and enhance the biological functions of EPCs. The effects of HGF transfection on proliferation, migration and angiogenesis of EPCs were investigated. Additionally, the role of ERK1/2 in this process was evaluated through the observation of ERK1/2 and ERK1/2 phosphorylation as well as by pharmacological analysis. Finally, we evaluated the effect of HGF-transfected EPCs (HGF-EPCs) on neointima formation after balloon-induced arterial injury in hypercholesterolemic rats. Our data showed that EPCs transfected with the HGF gene released high levels of soluble HGF protein, which were maintained for at least nine days. Transfection with HGF also enhanced the proliferative, migratory and angiogenic capabilities of EPCs, and promoted the activation of ERK1/2 without affecting its expression. ERK1/2 blockade by the chemical inhibitor PD98059 partially inhibited these effects. In hypercholesterolemic rats, HGF-EPCs homed to the site of vascular injury at a significantly higher rate than did EPCs without the exogenous HGF gene. Furthermore, systemically applied HGF-EPCs were more effective in decreasing neointima formation and increasing re-endothelialization. These data suggest that gene delivery combined with EPC transplant may be a practical and promising therapy for the prevention of neointimal formation after vascular injury.
Song
Ming-Bao
MB
The Institute of Cardiovascular Disease of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China.
Yu
Xue-Jun
XJ
Zhu
Guang-Xu
GX
Chen
Jian-Fei
JF
Zhao
Gang
G
Huang
Lan
L
D000704:Analysis of Variance; D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D001854:Bone Marrow Cells; D002318:Cardiovascular Diseases / Q000628:therapy; D020212:Carotid Artery Injuries / Q000628:therapy*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D042783:Endothelial Cells / Q000201:enzymology / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006937:Hypercholesterolemia / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000201:enzymology / Q000502:physiology*; D014162:Transfection; D017539:Tunica Intima / Q000473:pathology / Q000503:physiopathology
D002791:Cholesterol, Dietary; C066855:HGF protein, human; D011993:Recombinant Fusion Proteins; D017228:Hepatocyte Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases