Erythropoietin stimulates normal endothelial progenitor cell-mediated endothelial turnover, but attributes to neovascularization only in the presence of local ischemia

B Daan Westenbrink; Hisko Oeseburg; Lennaert Kleijn; Pim van der Harst; Anne M S Belonje; Adriaan A Voors; Regien G Schoemaker; Rudolf A de Boer; Dirk J van Veldhuisen; Wiek H van Gilst

doi:10.1007/s10557-008-6094-y

Erythropoietin stimulates normal endothelial progenitor cell-mediated endothelial turnover, but attributes to neovascularization only in the presence of local ischemia

B Daan Westenbrink, Hisko Oeseburg, Lennaert Kleijn, Pim van der Harst, Anne M S Belonje, Adriaan A Voors, Regien G Schoemaker, Rudolf A de Boer, Dirk J van Veldhuisen, Wiek H van Gilst

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

PURPOSE: 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.

Original language	English
Pages (from-to)	265-74
Number of pages	10
Journal	Cardiovascular Drugs and Therapy
Volume	22
Issue number	4
DOIs	https://doi.org/10.1007/s10557-008-6094-y
Publication status	Published - Aug 2008
Externally published	Yes

Keywords

Alkaline Phosphatase
Angiogenesis Inducing Agents/pharmacology
Animals
Bone Marrow Transplantation
Capillaries/drug effects
Cell Movement/drug effects
Coronary Vessels/drug effects
Darbepoetin alfa
Disease Models, Animal
Endothelial Cells/drug effects
Erythropoietin/analogs & derivatives
GPI-Linked Proteins
Heart Failure/drug therapy
Humans
Isoenzymes/genetics
Male
Myocardial Contraction/drug effects
Myocardial Infarction/complications
Myocardium/pathology
Neovascularization, Physiologic/drug effects
Rats
Rats, Inbred F344
Rats, Transgenic
Stem Cells/drug effects
Vasodilation/drug effects
Ventricular Function, Left/drug effects
Ventricular Pressure/drug effects

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10.1007/s10557-008-6094-y

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Westenbrink, B. D., Oeseburg, H., Kleijn, L., van der Harst, P., Belonje, A. M. S., Voors, A. A., Schoemaker, R. G., de Boer, R. A., van Veldhuisen, D. J., & van Gilst, W. H. (2008). Erythropoietin stimulates normal endothelial progenitor cell-mediated endothelial turnover, but attributes to neovascularization only in the presence of local ischemia. Cardiovascular Drugs and Therapy, 22(4), 265-74. https://doi.org/10.1007/s10557-008-6094-y

@article{db52da7fbe1c414a8f4be26790240d03,

title = "Erythropoietin stimulates normal endothelial progenitor cell-mediated endothelial turnover, but attributes to neovascularization only in the presence of local ischemia",

abstract = "PURPOSE: 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.",

keywords = "Alkaline Phosphatase, Angiogenesis Inducing Agents/pharmacology, Animals, Bone Marrow Transplantation, Capillaries/drug effects, Cell Movement/drug effects, Coronary Vessels/drug effects, Darbepoetin alfa, Disease Models, Animal, Endothelial Cells/drug effects, Erythropoietin/analogs & derivatives, GPI-Linked Proteins, Heart Failure/drug therapy, Humans, Isoenzymes/genetics, Male, Myocardial Contraction/drug effects, Myocardial Infarction/complications, Myocardium/pathology, Neovascularization, Physiologic/drug effects, Rats, Rats, Inbred F344, Rats, Transgenic, Stem Cells/drug effects, Vasodilation/drug effects, Ventricular Function, Left/drug effects, Ventricular Pressure/drug effects",

author = "Westenbrink, {B Daan} and Hisko Oeseburg and Lennaert Kleijn and {van der Harst}, Pim and Belonje, {Anne M S} and Voors, {Adriaan A} and Schoemaker, {Regien G} and {de Boer}, {Rudolf A} and {van Veldhuisen}, {Dirk J} and {van Gilst}, {Wiek H}",

year = "2008",

month = aug,

doi = "10.1007/s10557-008-6094-y",

language = "English",

volume = "22",

pages = "265--74",

journal = "Cardiovascular Drugs and Therapy",

issn = "0920-3206",

publisher = "Kluwer Academic Publishers",

number = "4",

}

Westenbrink, BD, Oeseburg, H, Kleijn, L, van der Harst, P, Belonje, AMS, Voors, AA, Schoemaker, RG, de Boer, RA, van Veldhuisen, DJ & van Gilst, WH 2008, 'Erythropoietin stimulates normal endothelial progenitor cell-mediated endothelial turnover, but attributes to neovascularization only in the presence of local ischemia', Cardiovascular Drugs and Therapy, vol. 22, no. 4, pp. 265-74. https://doi.org/10.1007/s10557-008-6094-y

Erythropoietin stimulates normal endothelial progenitor cell-mediated endothelial turnover, but attributes to neovascularization only in the presence of local ischemia. / Westenbrink, B Daan; Oeseburg, Hisko; Kleijn, Lennaert et al.
In: Cardiovascular Drugs and Therapy, Vol. 22, No. 4, 08.2008, p. 265-74.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Erythropoietin stimulates normal endothelial progenitor cell-mediated endothelial turnover, but attributes to neovascularization only in the presence of local ischemia

AU - Westenbrink, B Daan

AU - Oeseburg, Hisko

AU - Kleijn, Lennaert

AU - van der Harst, Pim

AU - Belonje, Anne M S

AU - Voors, Adriaan A

AU - Schoemaker, Regien G

AU - de Boer, Rudolf A

AU - van Veldhuisen, Dirk J

AU - van Gilst, Wiek H

PY - 2008/8

Y1 - 2008/8

N2 - PURPOSE: 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.

AB - PURPOSE: 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.

KW - Alkaline Phosphatase

KW - Angiogenesis Inducing Agents/pharmacology

KW - Animals

KW - Bone Marrow Transplantation

KW - Capillaries/drug effects

KW - Cell Movement/drug effects

KW - Coronary Vessels/drug effects

KW - Darbepoetin alfa

KW - Disease Models, Animal

KW - Endothelial Cells/drug effects

KW - Erythropoietin/analogs & derivatives

KW - GPI-Linked Proteins

KW - Heart Failure/drug therapy

KW - Humans

KW - Isoenzymes/genetics

KW - Male

KW - Myocardial Contraction/drug effects

KW - Myocardial Infarction/complications

KW - Myocardium/pathology

KW - Neovascularization, Physiologic/drug effects

KW - Rats

KW - Rats, Inbred F344

KW - Rats, Transgenic

KW - Stem Cells/drug effects

KW - Vasodilation/drug effects

KW - Ventricular Function, Left/drug effects

KW - Ventricular Pressure/drug effects

U2 - 10.1007/s10557-008-6094-y

DO - 10.1007/s10557-008-6094-y

M3 - Article

C2 - 18327705

SN - 0920-3206

VL - 22

SP - 265

EP - 274

JO - Cardiovascular Drugs and Therapy

JF - Cardiovascular Drugs and Therapy

IS - 4

ER -

Erythropoietin stimulates normal endothelial progenitor cell-mediated endothelial turnover, but attributes to neovascularization only in the presence of local ischemia

Abstract

Keywords

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