Recombinant α2(IV)NC1 domain of type IV collagen is an effective regulator of retinal capillary endothelial cell proliferation and inhibits pre-retinal neovascularisation |
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Authors: | Gary Coleman Tom A Gardiner Ariel Boutaud Alan W Stitt |
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Institution: | (1) Centre for Vision Science, School of Biomedical Science, Queen’s University Belfast, Royal Victoria Hospital, Grosvenor Road, Belfast, BT12 6BA, Northern Ireland, UK;(2) BioStratum Incorporated, Durham, NC, USA |
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Abstract: | Background A recombinant form of the α2(IV)NC1 domain of type IV collagen has been shown to have potent anti-angiogenic activity although
this peptide has not been studied in the context of proliferative retinopathies. In the current investigation we examined
the potential for α2(IV)NC1 to regulate retinal microvascular endothelial cell function using a range of in vitro and in vivo
assay systems.
Materials and methods α2(IV)NC1 at concentrations between 0.1 and 1 μg/ml was added to retinal microvascular endothelial cells (RMECs) followed
by assessment of cell attachment, proliferation and survival. This agent was also tested within a novel in vitro three-dimensional
retinal angiogenesis assay and the number of angiogenic sprouts quantified. α2(IV)NC1 was also delivered intra-vitreally to
mice with oxygen-induced proliferative retinopathy (OIR) and neovascularisation evaluated in comparison with vehicle-treated
controls.
Results RMECs treated with α2(IV)NC1 (0.1, 0.5 and 1 μg/ml) showed delayed attachment at 3 h post-seeding, although this deficit had
been restored at the 6-h time point. BrdU assay of DNA replication revealed that confluent RMECs treated with α2(IV)NC1 showed
no measurable response in comparison with vehicle-treated controls. By contrast, proliferation of sub-confluent RMECs was
significantly reduced by α2(IV)NC1 at 0.5 μg/ml (P<0.01). α2(IV)NC1 also induced apoptosis in RMECs and inhibited angiogenesis of pre-existing retinal vascular networks in
vitro (P<0.001). Intra-vitreal injection of α2(IV)NC1 in the OIR model significantly inhibited pre-retinal neovascularisation compared
with vehicle-treated controls (P<0.001).
Conclusion α2(IV)NC1 inhibits angiogenesis in the retinal microvasculature. This recombinant protein has potential for the treatment
of neovascularisation in proliferative retinopathies.
BioStratum Inc. did not sponsor this research in any way. None of the authors are paid consultants with this company. |
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Keywords: | Proliferative retinopathy Retinal microvascular endothelium α (2(IV)NC1 Neovascularisation |
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