Abstract
Purpose: :
Vitreous neovascularization is a major cause of blindness in ischemic retinopathies. The aim of this study was to investigate the therapeutic potential and mechanism of action of normobaric hyperoxia therapy in an animal model of ischemic retinopathy.
Methods: :
Oxygen-induced retinopathy (OIR) was induced by exposing C57BL/6J mice to 75% oxygen from postnatal day (P) 7 to P12 followed by return to room air. To investigate the effect of hyperoxia treatment (HT), OIR mice were returned to 75% oxygen on P14. mRNA levels of angiogenic, inflammatory and proteolytic molecules were determined by quantitative PCR (q-PCR) at P17 and P20 in OIR, HT, and room air (RA) controls. Retinal vasculature and astrocyte morphology were examined immunocytochemically using retinal wholemounts labeled with isolectin B4 and GFAP respectively.
Results: :
OIR caused increased expression of genes known to be involved in the pathological angiogenesis, including angiogenic molecules (VEGF, bFGF, PDGF-b, angiopoiten-2), inflammatory molecules (TNF-α, ICAM-1, iNOS, MCP-1) and proteolytic molecules (uPAR, PAI-1). These increases were reduced or eliminated by HT (P<0.001). Astrocyte degeneration in OIR was markedly reduced by HT allowing rapid reformation of the astrocytic template. Although vitreous neovascularization was essentially completely eliminated by HT (p<0.01 compared to OIR), physiologic revascularization was greatly accelerated compared to OIR at P20 (11.6% avascular area in HT vs. 23% in OIR, p<0.01). HT also increased the number of capillary endothelia tip cells extending into the avascular retina.
Conclusions: :
Hyperoxia treatment prevents pathological angiogenesis and accelerates physiological revascularization in OIR. At a cellular level these effects may be caused by the rescue of astrocytes. At a molecular level, HT caused decreased expression of proangiogenic growth factors, inflammatory mediators, and proteolytic molecules. These data suggest that normobaric oxygen therapy may be a clinically effective intervention to promote revascularization and prevent vitreous neovascularization in ischemic retinopathy.
Keywords: retinal neovascularization • oxygen • retinopathy of prematurity