title: Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization.
abstract: OBJECTIVE
  Erythropoietin (EPO) improves cardiac function and induces neovascularization in chronic heart failure (CHF), although the exact mechanism has not been elucidated. We studied the effects of EPO on homing and incorporation of endothelial progenitor cells (EPC) into the myocardial microvasculature and myocardial expression of angiogenic factors.
  
  
  RESULTS
  CHF was induced in rats by coronary artery ligation resulting in myocardial infarction (MI) after bone marrow had been replaced by human placental alkaline phosphatase (hPAP) transgenic cells. We studied the effects of darbepoetin alfa treatment (EPO, 40 microg/kg, every 3 weeks, starting 3 weeks after MI) on longitudinal changes in left ventricular (LV) function, circulating EPC, myocardial histology, and expression of vascular endothelial growth factor (VEGF) determined 9 weeks after MI. EPO prevented LV-dilatation and improved cardiac function (all P < 0.05), which was associated with 42% increased capillary growth (P < 0.01). EPO-induced mobilization of EPC from the bone marrow (P < 0.01), which resulted in a three-fold increased homing of EPC into the cardiac microvasculature. The percentage of the endothelium that consisted of bone marrow derived cells was significantly increased (3.9 +/- 0.5 vs. 11.4 +/- 1%, P < 0.001) comprising 30% of the newly formed capillaries. In addition, EPO treatment resulted in a 4.5-fold increased myocardial expression of VEGF, which correlated strongly with neovascularization (r = 0.67; P < 0.001). VEGF was equally expressed by endothelial cells of myocardial and bone marrow origin.
  
  
  CONCLUSIONS
  EPO-induced neovascularization in post-MI heart failure is mediated through a combination of EPC recruitment from the bone marrow and increased myocardial expression of VEGF.
authors.affiliation: Department of Cardiology, Thoraxcenter, University Medical Center Groningen, University of Groningen, Hanzeplein 1, PO 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: Erik
authors.initials: E
authors.lastname: Lipsic
authors.forename: Peter
authors.initials: P
authors.lastname: van der Meer
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.forename: Hisko
authors.initials: H
authors.lastname: Oeseburg
authors.forename: Gideon J
authors.initials: GJ
authors.lastname: Du Marchie Sarvaas
authors.forename: Johan
authors.initials: J
authors.lastname: Koster
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Voors
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: van Veldhuisen
authors.forename: Wiek H
authors.initials: WH
authors.lastname: van Gilst
authors.forename: Regien G
authors.initials: RG
authors.lastname: Schoemaker
mesh_terms: D000818:Animals; D002196:Capillaries / Q000378:metabolism; D003097:Collateral Circulation; D000068256:Darbepoetin alfa; D004452:Echocardiography; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects*; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006333:Heart Failure; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D013234:Stem Cells / Q000502:physiology*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000517:prevention & control
chemical_list: D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D000068256:Darbepoetin alfa