Vascular endothelial growth factor is crucial for erythropoietin-induced improvement of cardiac function in heart failure

B. Daan Westenbrink, Willem Peter T Ruifrok, Adriaan A. Voors, Ronald Tilton, Dirk J. Van Veldhuisen, Regien G. Schoemaker, Wiek H. Van Gilst, Rudolf A. De Boer

Research output: Contribution to journalArticle

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Abstract

Aims We intended to delineate the mechanisms of erythropoietin (EPO)-induced cardiac vascular endothelial growth factor (VEGF) production and to establish if VEGF is crucial for EPO-induced improvement of cardiac performance. Methods and resultsThe effects of EPO on VEGF expression were studied in cultured cardiac cells and EPO-treated hearts. The role of VEGF in EPO-induced neovascularization was studied with two distinct VEGF-neutralizing antibodies or irrelevant control IgG in an aortic sprouting assay and in rats with heart failure (HF) after myocardial infarction (MI) treated with EPO. EPO-alfa (10 IU/mL) was used in vitro and darbepoetin alfa (40 g/kg/3 weeks, starting 3 weeks after MI) in vivo. EPO stimulated VEGF mRNA expression through the signal transducers and activators of transcription-3 (STAT-3) pathway in neonatal rat cardiomyocytes, but not in endothelial cells or fibroblasts. Similarly, the direct effects of EPO on endothelial sprouting were modest and VEGF independent. In rats with HF, EPO increased VEGF protein expression predominantly in cardiomyocytes, associated with a 37 increase in capillary density and improved cardiac performance. Administration of VEGF-neutralizing antibodies abrogated the salutary effects of EPO on cardiac microvascularization and function. VEGF neutralization attenuated EPO-induced proliferation of myocardial endothelial cells and reduced myocardial incorporation of endothelial progenitor cells (EPCs) in rats with alkaline phosphatase-labelled bone marrow cells. Conclusion VEGF is crucial for EPO-induced improvement of cardiac function in HF. EPO fosters VEGF expression predominantly in cardiomyocytes, which in turn stimulates myocardial endothelial proliferation and incorporation of EPCs.

Original languageEnglish (US)
Pages (from-to)30-39
Number of pages10
JournalCardiovascular Research
Volume87
Issue number1
DOIs
StatePublished - Jul 1 2010

Fingerprint

Erythropoietin
Vascular Endothelial Growth Factor A
Heart Failure
Cardiac Myocytes
Neutralizing Antibodies
Endothelial Cells
Myocardial Infarction
STAT3 Transcription Factor
Bone Marrow Cells
Alkaline Phosphatase
Cultured Cells
Fibroblasts
Immunoglobulin G

Keywords

  • Cardiac function
  • Erythropoietin
  • Heart failure
  • Neovascularization
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology
  • Medicine(all)

Cite this

Westenbrink, B. D., Ruifrok, W. P. T., Voors, A. A., Tilton, R., Van Veldhuisen, D. J., Schoemaker, R. G., ... De Boer, R. A. (2010). Vascular endothelial growth factor is crucial for erythropoietin-induced improvement of cardiac function in heart failure. Cardiovascular Research, 87(1), 30-39. https://doi.org/10.1093/cvr/cvq041

Vascular endothelial growth factor is crucial for erythropoietin-induced improvement of cardiac function in heart failure. / Westenbrink, B. Daan; Ruifrok, Willem Peter T; Voors, Adriaan A.; Tilton, Ronald; Van Veldhuisen, Dirk J.; Schoemaker, Regien G.; Van Gilst, Wiek H.; De Boer, Rudolf A.

In: Cardiovascular Research, Vol. 87, No. 1, 01.07.2010, p. 30-39.

Research output: Contribution to journalArticle

Westenbrink, BD, Ruifrok, WPT, Voors, AA, Tilton, R, Van Veldhuisen, DJ, Schoemaker, RG, Van Gilst, WH & De Boer, RA 2010, 'Vascular endothelial growth factor is crucial for erythropoietin-induced improvement of cardiac function in heart failure', Cardiovascular Research, vol. 87, no. 1, pp. 30-39. https://doi.org/10.1093/cvr/cvq041
Westenbrink, B. Daan ; Ruifrok, Willem Peter T ; Voors, Adriaan A. ; Tilton, Ronald ; Van Veldhuisen, Dirk J. ; Schoemaker, Regien G. ; Van Gilst, Wiek H. ; De Boer, Rudolf A. / Vascular endothelial growth factor is crucial for erythropoietin-induced improvement of cardiac function in heart failure. In: Cardiovascular Research. 2010 ; Vol. 87, No. 1. pp. 30-39.
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abstract = "Aims We intended to delineate the mechanisms of erythropoietin (EPO)-induced cardiac vascular endothelial growth factor (VEGF) production and to establish if VEGF is crucial for EPO-induced improvement of cardiac performance. Methods and resultsThe effects of EPO on VEGF expression were studied in cultured cardiac cells and EPO-treated hearts. The role of VEGF in EPO-induced neovascularization was studied with two distinct VEGF-neutralizing antibodies or irrelevant control IgG in an aortic sprouting assay and in rats with heart failure (HF) after myocardial infarction (MI) treated with EPO. EPO-alfa (10 IU/mL) was used in vitro and darbepoetin alfa (40 g/kg/3 weeks, starting 3 weeks after MI) in vivo. EPO stimulated VEGF mRNA expression through the signal transducers and activators of transcription-3 (STAT-3) pathway in neonatal rat cardiomyocytes, but not in endothelial cells or fibroblasts. Similarly, the direct effects of EPO on endothelial sprouting were modest and VEGF independent. In rats with HF, EPO increased VEGF protein expression predominantly in cardiomyocytes, associated with a 37 increase in capillary density and improved cardiac performance. Administration of VEGF-neutralizing antibodies abrogated the salutary effects of EPO on cardiac microvascularization and function. VEGF neutralization attenuated EPO-induced proliferation of myocardial endothelial cells and reduced myocardial incorporation of endothelial progenitor cells (EPCs) in rats with alkaline phosphatase-labelled bone marrow cells. Conclusion VEGF is crucial for EPO-induced improvement of cardiac function in HF. EPO fosters VEGF expression predominantly in cardiomyocytes, which in turn stimulates myocardial endothelial proliferation and incorporation of EPCs.",
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AU - Westenbrink, B. Daan

AU - Ruifrok, Willem Peter T

AU - Voors, Adriaan A.

AU - Tilton, Ronald

AU - Van Veldhuisen, Dirk J.

AU - Schoemaker, Regien G.

AU - Van Gilst, Wiek H.

AU - De Boer, Rudolf A.

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N2 - Aims We intended to delineate the mechanisms of erythropoietin (EPO)-induced cardiac vascular endothelial growth factor (VEGF) production and to establish if VEGF is crucial for EPO-induced improvement of cardiac performance. Methods and resultsThe effects of EPO on VEGF expression were studied in cultured cardiac cells and EPO-treated hearts. The role of VEGF in EPO-induced neovascularization was studied with two distinct VEGF-neutralizing antibodies or irrelevant control IgG in an aortic sprouting assay and in rats with heart failure (HF) after myocardial infarction (MI) treated with EPO. EPO-alfa (10 IU/mL) was used in vitro and darbepoetin alfa (40 g/kg/3 weeks, starting 3 weeks after MI) in vivo. EPO stimulated VEGF mRNA expression through the signal transducers and activators of transcription-3 (STAT-3) pathway in neonatal rat cardiomyocytes, but not in endothelial cells or fibroblasts. Similarly, the direct effects of EPO on endothelial sprouting were modest and VEGF independent. In rats with HF, EPO increased VEGF protein expression predominantly in cardiomyocytes, associated with a 37 increase in capillary density and improved cardiac performance. Administration of VEGF-neutralizing antibodies abrogated the salutary effects of EPO on cardiac microvascularization and function. VEGF neutralization attenuated EPO-induced proliferation of myocardial endothelial cells and reduced myocardial incorporation of endothelial progenitor cells (EPCs) in rats with alkaline phosphatase-labelled bone marrow cells. Conclusion VEGF is crucial for EPO-induced improvement of cardiac function in HF. EPO fosters VEGF expression predominantly in cardiomyocytes, which in turn stimulates myocardial endothelial proliferation and incorporation of EPCs.

AB - Aims We intended to delineate the mechanisms of erythropoietin (EPO)-induced cardiac vascular endothelial growth factor (VEGF) production and to establish if VEGF is crucial for EPO-induced improvement of cardiac performance. Methods and resultsThe effects of EPO on VEGF expression were studied in cultured cardiac cells and EPO-treated hearts. The role of VEGF in EPO-induced neovascularization was studied with two distinct VEGF-neutralizing antibodies or irrelevant control IgG in an aortic sprouting assay and in rats with heart failure (HF) after myocardial infarction (MI) treated with EPO. EPO-alfa (10 IU/mL) was used in vitro and darbepoetin alfa (40 g/kg/3 weeks, starting 3 weeks after MI) in vivo. EPO stimulated VEGF mRNA expression through the signal transducers and activators of transcription-3 (STAT-3) pathway in neonatal rat cardiomyocytes, but not in endothelial cells or fibroblasts. Similarly, the direct effects of EPO on endothelial sprouting were modest and VEGF independent. In rats with HF, EPO increased VEGF protein expression predominantly in cardiomyocytes, associated with a 37 increase in capillary density and improved cardiac performance. Administration of VEGF-neutralizing antibodies abrogated the salutary effects of EPO on cardiac microvascularization and function. VEGF neutralization attenuated EPO-induced proliferation of myocardial endothelial cells and reduced myocardial incorporation of endothelial progenitor cells (EPCs) in rats with alkaline phosphatase-labelled bone marrow cells. Conclusion VEGF is crucial for EPO-induced improvement of cardiac function in HF. EPO fosters VEGF expression predominantly in cardiomyocytes, which in turn stimulates myocardial endothelial proliferation and incorporation of EPCs.

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KW - Erythropoietin

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KW - Neovascularization

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