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F. Mowat, P. Kelly, Y. Duran, A. Smith, J. Leiper, P. Vallance, R. R. Ali, J. Bainbridge; The Role of DDAH 1 in Retinal Vascular Development and Disease.. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3422.
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Pathological angiogenesis is common to the major causes of vision loss. Nitric oxide (NO) is pro-angiogenic in the retina and choroid, and may act independently of VEGF. Production of NO is controlled by Nitric Oxide Synthase (NOS), expressed in 3 major isoforms with significant tissue-specificity. NO production is promoted by dimethylarginine dimethylaminohydrolase (DDAH), which metabolises the NOS inhibitor asymmetrically methylated arginine. Two DDAH isoforms (DDAH1 and 2) have similar catalytic activities, but contrasting tissue distributions. The purpose of this study was to determine the role of DDAH1 in retinal vascular development and pathological retinal angiogenesis.
The DDAH1 knockout mouse is embryonically lethal; heterozygous animals have vascular endothelial cell dysfunction and develop pulmonary hypertension. We examined heterozygous animals by funduscopy, fluorescein angiography and electroretinography. We investigated the effect of DDAH1 on pathological retinal angiogenesis using a mouse model of ischaemia-induced retinal neovascularisation.
Real time PCR analysis of DDAH1 and 2 expression in ischaemic retinopathy in wild-type mice demonstrated that DDAH1 is moderately reduced during hyperoxia, but expression of neither DDAH1 nor 2 are altered during retinal ischaemia. We identified no abnormality of ocular vascular development or retinal function in DDAH1 heterozygous knockout mice. In the mouse model of ischemic retinopathy, heterozygous knockout of DDAH1 had no significant effect on ischemia or neovascularisation.
This study demonstrates that despite significant changes in endothelial cell function, heterozygous knockout of DDAH1 has no apparent effect on ocular vascular development or ischaemic retinopathy. DDAH2, which has a specifically vascular distribution, may have a more important role in retinal vascular disease.
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