Differential modulation of angiogenesis by erythropoiesis-stimulating agents in a mouse model of ischaemic retinopathy.
BACKGROUND
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.


RESULTS
The 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 TNFalpha and VEGF mRNA expression which were up to 4 fold higher than with epoetin delta (p<0.001).


CONCLUSIONS
This study has implications for treatment of patients as there are clear differences in the angiogenic potential of the different ESAs.
McVicar
Carmel M
CM
Centre for Vision and Vascular Science, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.
Colhoun
Liza M
LM
Abrahams
Jodie L
JL
Kitson
Claire L
CL
Hamilton
Ross
R
Medina
Reinhold J
RJ
Durga
Dash
D
Gardiner
Tom A
TA
Rudd
Pauline M
PM
Stitt
Alan W
AW
D000818:Animals; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000627:therapeutic use; D006397:Hematinics / Q000627:therapeutic use*; D007511:Ischemia / Q000150:complications*; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000209:etiology; D011994:Recombinant Proteins; D012160:Retina / Q000473:pathology / Q000648:ultrastructure; D012164:Retinal Diseases / Q000188:drug therapy* / Q000209:etiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D006397:Hematinics; D011994:Recombinant Proteins; C103998:epoetin beta; D004921:Erythropoietin; C516023:epoetin delta