Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization

B. Daan Westenbrink*, Erik Lipsic, Peter van der Meer, Pirn van der Harst, Hisko Oeseburg, Gideon J. Du Marchie Sarvaas, Johan Koster, Adriaan A. Voors, Dirk J. van Veldhuisen, Wiek H. van Gilst, Regien G. Schoemaker

*Corresponding author for this work

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Abstract

Aims Erythropoietin (EPO) improves cardiac function and induces neovascutarization 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.

Methods and 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CHF was induced in rats by coronary artery ligation resulting in myocardial infarction (MI) after bone marrow had been replaced by human placental alkaline phosphatase (hPAP) transgenic cells.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 mu g/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 W-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 neovascutarization (r = 0.67; P <0.001). VEGF was equally expressed by endothelial cells of myocardial and bone marrow origin.

Conclusion 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.

Original languageEnglish
Pages (from-to)2018-2027
Number of pages10
JournalEuropean Heart Journal
Volume28
Issue number16
DOIs
Publication statusPublished - Aug-2007

Keywords

  • erythropoietin
  • endothelial progenitor cell
  • neovascularization
  • chronic heart failure
  • DOXORUBICIN-INDUCED CARDIOMYOPATHY
  • ANALOG DARBEPOETIN-ALPHA
  • MYOCARDIAL-INFARCTION
  • HEART-FAILURE
  • ENDOGENOUS ERYTHROPOIETIN
  • RATS
  • ISCHEMIA/REPERFUSION
  • DETERMINANTS
  • ANGIOGENESIS
  • DYSFUNCTION

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