Abstract
BackgroundErythropoiesis stimulating agents (ESAs) are widely used to treat anaemia but concerns exist about their potential to promote pathological angiogenesis in some clinical scenarios. In the current study we have assessed the angiogenic potential of three ESAs; epoetin delta, darbepoetin alfa and epoetin beta using in vitro and in vivo models.Methodology/Principal FindingsThe epoetins induced angiogenesis in human microvascular endothelial cells at high doses, although darbepoetin alfa was pro-angiogenic at low-doses (1–20 IU/ml). ESA-induced angiogenesis was VEGF-mediated. In a mouse model of ischaemia-induced retinopathy, all ESAs induced generation of reticulocytes but only epoetin beta exacerbated pathological (pre-retinal) neovascularisation in comparison to controls (p<0.05). Only epoetin delta induced a significant revascularisation response which enhanced normality of the vasculature (p<0.05). This was associated with mobilisation of haematopoietic stem cells and their localisation to the retinal vasculature. Darbepoetin alfa also increased the number of active microglia in the ischaemic retina relative to other ESAs (p<0.05). Darbepoetin alfa induced retinal TNFα and VEGF mRNA expression which were up to 4 fold higher than with epoetin delta (p<0.001).ConclusionsThis study has implications for treatment of patients as there are clear differences in the angiogenic potential of the different ESAs.
Highlights
Hypoxia-mediated secretion of erythropoietin (EPO) from the kidney maintains erythrocyte mass through inhibition of apoptosis in bone marrow precursors
EPO is expressed in many organs where it can activate the EPO receptor (EPO-R), sometimes in combination with the b-common receptor [2]
We describe how the angiogenic potential of the human cell-derived Epoetin Delta differs from recombinant EPOs darbepoetin alfa, epoetin beta derived from CHO cells and that these Erythropoiesis stimulating agents (ESAs) have differential impacts on ischaemic retina
Summary
Hypoxia-mediated secretion of erythropoietin (EPO) from the kidney maintains erythrocyte mass through inhibition of apoptosis in bone marrow precursors. EPO is expressed in many organs where it can activate the EPO receptor (EPO-R), sometimes in combination with the b-common receptor (bCR; CD131) [2]. This tissue protective role is exemplified during ischaemic brain injury in which hypoxia inducible factor (HIF-1a) regulates EPO expression and serves to reduce infarct size [3]. It has been demonstrated that administration of exogenous human recombinant rHuEPO to pre-clinical models of ischaemic injury can significantly reduce neurodegeneration by preventing neuro-glial apoptosis [4]. Erythropoiesis stimulating agents (ESAs) are widely used to treat anaemia but concerns exist about their potential to promote pathological angiogenesis in some clinical scenarios. In the current study we have assessed the angiogenic potential of three ESAs; epoetin delta, darbepoetin alfa and epoetin beta using in vitro and in vivo models
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
