title: Endothelial progenitor cells may inhibit apoptosis of pulmonary microvascular endothelial cells: new insights into cell therapy for pulmonary arterial hypertension.
abstract: OBJECTIVE
  Endothelial apoptosis underlies the pathophysiology of pulmonary arterial hypertension (PAH). Some factors/cytokines released by endothelial progenitor cells (EPC) have been revealed as potent inhibitors of apoptosis. The aim of this study was to investigate the effects of EPC on pulmonary microvascular endothelial cell (PMVEC) survival with the PAH condition.
  
  
  METHODS
  PMVEC apoptosis was induced by high shear stress (HSS) with serum starvation or pro-inflammatory factors in an artificial capillary system. EPC were delivered into monocrotaline-induced PAH nude rats.
  
  
  RESULTS
  PMVEC apoptosis under HSS and serum starvation conditions was significantly inhibited by EPC conditioned medium (CM). It was attenuated by vascular endothelial growth factor (VEGF)-A or -B blocking. EPC CM promoted PMVEC proliferation, which was weakened by VEGF-A or interleukin (IL)-8 blocking. The EPC CM caused less apoptosis of PMVEC induced by HSS plus pro-inflammatory factors. The anti-apoptotic effect of EPC CM was attenuated by blockade of either vascular endothelial growth factor receptor (VEGFR)-1 or -2. However, the pro-proliferating effect appeared to be weakened only by VEGFR-2 blocking. Both Erk1/2 and Akt phosphorylation were enhanced by EPC CM. VEGFR-2 blockage led to significant inhibition of Erk1/2 and Akt activation; VEGFR-1 blockage only of Erk1/2 activation. Human-origin VEGF co-localized with incorporated EPC in small pulmonary arterioles, and EPC transplantation resulted in down-regulation of caspase-3 expression.
  
  
  CONCLUSIONS
  The VEGF-A/B-VEGFR-1/2-Erk1/2 signal pathway took major responsibility for the anti-apoptotic effects of EPC on PMVEC, and VEGF-A-VEGFR-2-Akt for pro-proliferating effects. Growth factors, secreted in a paracrine manner by transplanted EPC, inhibited cell apoptosis in PAH lung.
authors.affiliation: Department of Cardiology, Sir Run Run Shaw Hospital, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xia
authors.forename: Guo-Sheng
authors.initials: GS
authors.lastname: Fu
authors.forename: Jin-Xiu
authors.initials: JX
authors.lastname: Yang
authors.forename: Fu-Rong
authors.initials: FR
authors.lastname: Zhang
authors.forename: Xing-Xiang
authors.initials: XX
authors.lastname: Wang
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D001160:Arterioles / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000201:enzymology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy*; D007249:Inflammation / Q000378:metabolism; D008168:Lung / Q000201:enzymology; D055806:Microvessels / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D044967:Serum; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D013314:Stress, Mechanical; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3