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; Harst, Pim van der; Belonje, Anne M.; Voors, Adriaan A.; Schoemaker, Regien G.; Boer, Rudolf A. de; Veldhuisen, Dirk J. van; Gilst, Wiek H. van

doi:10.1007/s10557-008-6094-y

Cited by 52 publications

(38 citation statements)

References 36 publications

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“…27 Moreover, EPO was able to stimulate normal endothelial progenitor cellmediated endothelial turnover, but the effect on cardiac microvascularization and function was only seen in the presence of ischemia. 29 This is in line with our results that show a formation of new microvessels in critically ischemic tissue in all animals with administered EPO independently from coadministration of L-Name, which suggests an EPOmediated angiogenic response under hypoxic conditions. Animals that simultaneously received EPO and bevacizumab showed a complete abrogation of the EPO-induced angiogenic response without affecting the EPO-mediated tissue protection.…”

Section: Epo Enos Ischemic Damage and Skin F Rezaeian Et Alsupporting

confidence: 91%

Erythropoietin-induced upregulation of endothelial nitric oxide synthase but not vascular endothelial growth factor prevents musculocutaneous tissue from ischemic damage

Rezaeian

Wettstein

Egger

et al. 2010

Laboratory Investigation

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Recent findings have attested the protective effects of erythropoietin (EPO) in ischemically challenged organs. We therefore aimed at elaborating the underlying mechanism of EPO-mediated protection in musculocutaneous tissue undergoing persistent ischemia after acute injury. Mice were assigned to five experimental groups equipped with a randomly perfused flap fixed in a dorsal skinfold chamber, whereas the sixth group did not undergo flap preparation: EPO, L-Name, EPO and L-Name, EPO and bevacizumab, untreated flap, and nonischemic chamber (control). Intravital fluorescence microscopic analysis of microhemodynamics, apoptotic cell death, macromolecular leakage and angiogenesis was carried out over a 10-day period. Further, immunohistochemical analysis was used to study the protein expression of endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF). Increased expression of eNOS in EPO-administered mice correlated with significant arteriolar dilation and thus increased blood flow resulting in a maintained functional capillary density (FCD) at day 10. In addition, EPO induced a VEGF upregulation, which was associated with newly formed capillaries. In addition, EPO was able to reduce ischemia-induced apoptotic cell death and finally to significantly reduce flap necrosis. In contrast, coadministration of L-Name abolished EPO-mediated tissue protection by abrogating the dilatory effect resulting in reduced FCD and tissue survival, without counteracting angiogenesis and apoptotic cell death, whereas additional administration of bevacizumab did not influence the beneficial effect of EPO on flap survival despite abrogating angiogenesis. Macromolecular leakage was found to be increased in all treatment groups. This study shows that EPO administration prevents musculocutaneous tissue from ischemic necrosis as a consequence of an eNOS-dependent arteriolar hyperperfusion maintaining capillary perfusion, thus representing a promising approach to pharmacologically protect ischemically challenged tissue.

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Section: Epo Enos Ischemic Damage and Skin F Rezaeian Et Alsupporting

confidence: 91%

Erythropoietin-induced upregulation of endothelial nitric oxide synthase but not vascular endothelial growth factor prevents musculocutaneous tissue from ischemic damage

Rezaeian

Wettstein

Egger

et al. 2010

Laboratory Investigation

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“…Erythropoietin-induced neovascularization in post-myocardial infarction heart failure therefore relies on a combination of endothelial progenitor cell recruitment from the bone marrow and increased myocardial expression of vascular endothelial growth factor. Moreover, the presence of ischemia is pivotal for EPO-induced myocardial regeneration, since EPO treatment in healthy rats does not affect cardiac function or improves microvascularization [58]. The effects of EPO on endothelial progenitor cells seem mediated through the AkteNOS pathway, whereas in situ endothelial proliferation has been linked to the Jak2-STAT3 and MAPK p38 pathways [59].…”

Section: Erythropoietin For Heart Failurementioning

confidence: 99%

Is there a role for erythropoietin in cardiovascular disease?

Vogiatzi

Briasoulis

Tousoulis

et al. 2009

Expert Opinion on Biological Therapy

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“…21 The treatment regiment used in this study was based on previous positive experience with DA treatment in the experimental setting in SD rats, where this dose of DA effectively raised haematocrit. 23,24 It may well be that one dose of DA every 3 weeks is less effective than when DA is administered more frequently and plasma concentrations of DA are being kept at a more constant level during the entire experiment.…”

Section: Discussionmentioning

confidence: 99%

Renal effects of long-term darbepoetin alpha treatment in hypertensive TGR(mRen2)27 rats

Frenay

Ruifrok

Bulthuis

et al. 2012

J Renin Angiotensin Aldosterone Syst

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Introduction: Erytropoietin (EPO) has cytoprotective and angiogenic properties and has a beneficial effect in ischaemic conditions. Since the development of renal interstitial abnormalities are often associated with ischaemia, we studied the effects of the long-acting EPO analogue darbepoetin alpha (DA) on kidney damage in TGR(mRen2)27 (Ren2) rats. Materials and methods: Ren2 rats were randomised to DA or vehicle (VEH) or to DA + angiotensin converting enzyme inhibitor (ACEi) or VEH + ACEi. Sprague Dawley (SD) rats served as controls. Blood pressure was measured weekly and 24-h urine was collected to measure proteinuria. Blood samples were collected for creatinine and haematocrit. Kidneys were studied for inflammation and pre-fibrosis. Renal mRNA expression was studied for EPO, EPO-receptor, collagen-3α1 and kidney injury molecule-1 (KIM-1). Results: DA had no effect on SBP, serum creatinine and proteinuria. Interstitial and glomerular α-SMA expression was significantly increased in Ren2. ACEi but not DA improved the increased renal inflammatory and pro-fibrotic profile in Ren2 rats. DA on top of ACEi further reduced glomerular α-SMA and KIM-1 expression. Conclusion: Long-term DA treatment has no beneficial effects on renal structural and functional changes in TGR(mRen2)27 rats in the time frame studied and the dose provided.

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Erythropoietin Stimulates Normal Endothelial Progenitor Cell-Mediated Endothelial Turnover, but Attributes to Neovascularization Only in the Presence of Local Ischemia

Abstract: In general, EPO stimulates normal endothelial progenitor cell-mediated endothelial turnover, but improves cardiac microvascularization and function only in the presence of ischemia.

Cited by 52 publications

References 36 publications

Erythropoietin-induced upregulation of endothelial nitric oxide synthase but not vascular endothelial growth factor prevents musculocutaneous tissue from ischemic damage

Erythropoietin-induced upregulation of endothelial nitric oxide synthase but not vascular endothelial growth factor prevents musculocutaneous tissue from ischemic damage

Is there a role for erythropoietin in cardiovascular disease?

Renal effects of long-term darbepoetin alpha treatment in hypertensive TGR(mRen2)27 rats

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