title: The therapeutic effect of vascular endothelial growth factor gene- or heme oxygenase-1 gene-modified endothelial progenitor cells on neovascularization of rat hindlimb ischemia model.
abstract: OBJECTIVE
  To explore the therapeutic potential of endothelial progenitor cells (EPCs) transfected with vascular endothelial growth factor A (VEGFA) and heme oxygenase-1 (HO-1) on rat hindlimb ischemia model.
  
  
  METHODS
  Eukaryotic expression vectors encoding VEGFA or HO-1 were constructed and introduced into EPCs isolated from rat bone marrow. In total, 150 Sprague Dawley rat hindlimb ischemia models were established and randomized into five groups which were injected via tail vein with phosphate-buffered saline (PBS), nontransfected EPCs, VEGFA-modified EPCs, HO-1-modified EPCs, and both VEGFA- and HO-1-modified EPCs, respectively. The microvessel density, the expressions of VEGFA and HO-1 in the ischemic limbs, the recovery of blood flow as evaluated by laser-Doppler perfusion imaging, and the rate of limb salvage were compared among different groups.
  
  
  RESULTS
  Transplantation of both VEGFA- and HO-1-modified EPCs in recipient rats significantly increased the microvessel density (expressed as capillaries/m(2) at day 21 after operation, group vascular endothelial growth factor (VEGF)+HO-1, 357 ± 14.1; group VEGF, 253.7 ± 9.9; group HO-1, 255.5 ± 12.5; group EPC, 210.7 ± 10.3; group PBS, 144.3 ± 9.3; P < .001), the expressions of VEGFA and HO-1 in ischemic tissue, the recovery of blood flow (at day 21, VEGF+HO-1 group, 85.4 ± 17.8%; VEGF group, 51.2 ± 13.2%; HO-1 group, 50.4 ± 12.9%; EPC group, 39.9 ± 8.5%; PBS group, 28.3 ± 7.8%; P < .001), and the rate of limb salvage (VEGF+HO-1 group, 94.4%; VEGF group or HO-1 group, 63.6%; EPC group, 50.0%; PBS group, 11.1%), compared with transplantation of either VEGFA- or HO-1-modified EPCs alone, or of nontransfected EPCs, or PBS injection. The order of therapeutic effectiveness on ischemic limbs was VEGFA- + HO-1-modifed EPC > either VEGFA- or HO-1-modified EPC alone > nontransfected EPC > PBS.
  
  
  CONCLUSIONS
  VEGFA-modified EPC and HO-1-modified EPC synergized with each other in promoting angiogenesis in ischemic limbs of rat hindlimb ischemia model. In addition to VEGF, the introduction of HO-1 in EPC-based transplantation may serve as a novel and useful therapeutic strategy for ischemic disease of lower extremity.
authors.affiliation: Department of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Jianting
authors.initials: J
authors.lastname: Long
authors.forename: Sanming
authors.initials: S
authors.lastname: Wang
authors.forename: Yuanqi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiangxia
authors.initials: X
authors.lastname: Liu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Shenming
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001783:Blood Flow Velocity; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology / Q000637:transplantation*; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000235:genetics; D006614:Hindlimb; D007511:Ischemia / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D017078:Laser-Doppler Flowmetry; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D012039:Regional Blood Flow; D033581:Stem Cell Transplantation; D013997:Time Factors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat