Neovascularisation occurs in response to tissue ischemia in conditions including ischaemic retinopathy, with new vessels often infiltrating the transparent vitreous by a poorly understood mechanism. Nitric oxide produced by eNOS is a downstream mediator of VEGF function and plays a crucial role in vascular formation and maturation; therefore, we investigated the role of NOS using transgenic models in the murine model of oxygen induced retinopathy (aiR). Using eNOS over-expressing eNOS-GFP mice, we investigated vascular growth during retinal development, during aiR and also using an in-vitro model and found that eNOS over-expression increased angiogenesis. Over-expression of eNOS in the eNOS-GFP mice resulted in an increase in vaso-obliteration following hyperoxia exposure, which was followed by an increased neovascular response and improved revascularisation of the ischaemic retina. There was evidence of dysfunction of NOS in the eNOS-GFP animals, with an increase in oxidative stress which may contribute to the neovascular formation. Using the BH4 deficient hph-l mouse model we investigated the role of this NOS co-factor in the development of the retinal vasculature and the pathology of ischaemic retinopathy. We found that there was a reduced severity of both the vaso-obliterative . and neovascular phases of ischaemic retinopathy. A reduction in NOS activity due to the BH4 deficiency was demonstrated in-vitro in microglial cells from the hph-l animals and could explain the reduced angiogenesis seen in the hph-l animals. Our results demonstrate that the pathology of ischaemic retinopathy is altered by changes in NOS expression and function with eNOS over-expression resulting in more severe vaso-obliteration, followed by improved retinal revascularisation, while a deficiency in BH4 results in reduced severity of both the vaso-obliterative and neovascular phases of ischaemic retinopathy, but with a delayed revascularisation. These results indicate that selective alteration of NOS expression at different stages of ischaemic retinopathy may reduce the severity of the vaso-obliterative stage and help promote recovery of the ischaemic retina.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:557406 |
| Date | January 2012 |
| Creators | Edgar, K. S. |
| Publisher | Queen's University Belfast |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
Page generated in 0.0079 seconds