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Denise M. McDonald, Kevin Edgar, Nuria Matesanz, Keith Channon, Tom A. Gardiner; The Effect Of Bh4 Deficiency In Ischemic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2556.
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Nitric oxide (NO) can have opposing functions in ischemic retinopathy as it can either impede or promote vascular recovery. These conflicting roles are believed to be dependent upon the enzymatic and cellular source of NO production; endothelial nitric oxide synthase (eNOS) in the endothelium or inducible NOS (iNOS), upregulated in reponse to hypoxia in Muller and microglial cells. All NOS isoforms require the cofactor tetrahydrobiopterin (BH4) for full activity and here using a murine model partially deficient in BH4 (hph-1) we investigated the role of BH4 in ischemic retinopathy.
Hph-1 mice and littermate controls were subject to oxygen-induced retinopathy (OIR) by exposure to 75% oxygen (postnatal days 7-12) and retinas collected at various time points following return to room air. Retinal cell death in the acute hypoxic phase (P13; high iNOS expression) was determined by TUNEL staining. Vascular growth in the proliferative phase of OIR (P17) was quantified by B simplicifolia isolectin staining of retinal flat mounts. Vascular growth was also determined in aortic explants cultured in Matrigel.
At P13 there was a significant decrease in the number of TUNEL positive apoptotic cells in the inner nuclear layer of the ischemic retina of the hph-1 group. In parallel, this group also demonstrated reduced retinal revascularisation and neovascularisation at P17. Accordingly, aortic explants also exhibited reduced tube formation reversible upon BH4 supplementation.
Collectively, our results demonstrate that BH4 deficiency attenuates angiogenic drive and vascular growth and also reduces hypoxia induced retinal damage.1Khoo et al Circulation 2005 111:2126-33.
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