title: Erythropoietin stimulates normal endothelial progenitor cell-mediated endothelial turnover, but attributes to neovascularization only in the presence of local ischemia.
abstract: OBJECTIVE
  We aimed to evaluate whether ischemia is required for erythropoietin (EPO) induced stimulation of endothelial progenitor cells (EPCs) and their related effects on endothelial and cardiac function.
  
  
  METHODS
  Bone marrow of rats was replaced by transgenic cells to allow tracking of EPCs. Ischemic heart failure was induced by left coronary artery ligation to induce myocardial infarction (MI) and control rats received a sham procedure. Three weeks after surgery, rats were randomized to receive EPO (darbepoetin alfa 40 microg/kg per 3 weeks) or vehicle and were sacrificed 9 weeks after surgery.
  
  
  RESULTS
  In all treated groups, EPO significantly increased circulating EPCs and their incorporation into the endothelium of the ischemic and non-ischemic hearts as well as in the control organs; kidney and liver. This was associated with significantly improved endothelial function, which was strongly correlated with circulating EPCs (R = 0.7, p < 0.01). However, additional EPCs preferentially homed to the ischemic MI borderzone (p < 0.01) resulting in specific EPO-induced improvement of cardiac microvascularization and performance only in ischemic hearts (all p < 0.05). The differential stimulation of neovascularization by EPO was associated with increased EPO-receptor and VEGF expression in ischemic hearts only.
  
  
  CONCLUSIONS
  In general, EPO stimulates normal endothelial progenitor cell-mediated endothelial turnover, but improves cardiac microvascularization and function only in the presence of ischemia.
authors.affiliation: Department of Cardiology, Thoraxcenter, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB Groningen, The Netherlands. b.d.westenbrink@thorax.umcg.nl
authors.forename: B Daan
authors.initials: BD
authors.lastname: Westenbrink
authors.forename: Hisko
authors.initials: H
authors.lastname: Oeseburg
authors.forename: Lennaert
authors.initials: L
authors.lastname: Kleijn
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.forename: Anne M S
authors.initials: AM
authors.lastname: Belonje
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Voors
authors.forename: Regien G
authors.initials: RG
authors.lastname: Schoemaker
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: van Veldhuisen
authors.forename: Wiek H
authors.initials: WH
authors.lastname: van Gilst
mesh_terms: D000469:Alkaline Phosphatase; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D016026:Bone Marrow Transplantation; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D000068256:Darbepoetin alfa; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology; D058851:GPI-Linked Proteins; D006333:Heart Failure / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D013234:Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D014664:Vasodilation / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D043925:Angiogenesis Inducing Agents; D058851:GPI-Linked Proteins; D007527:Isoenzymes; D004921:Erythropoietin; D000068256:Darbepoetin alfa; D000469:Alkaline Phosphatase; C019839:alkaline phosphatase, placental