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Alix Trouillet, Emmanuelle Plaisier, Brahim El Mathari, Henri Lorach, Ivana Ivkovic, Julie Degardin, Michel Paques, Pierre Ronco, Jose Alain Sahel, Serge A Picaud; Collagen 4a1 deficiency induces a vascular leakage in the retina. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6178.
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HANAC syndrome is an autosomal dominant hereditary angiopathy with nephropathy, aneurysms, and muscle cramps. People with HANAC syndrome can also experience occasional visual problems due to arterial retinal tortuosity, cataract or Axenfeld-Rieger abnormalities. It has been shown that a mutation in the gene COL4A1 is responsible for these symptoms. COL4A1 gene codes for a subtype of collagen protein mainly located in the basement membrane surrounding blood vessels. We recently found rod and cone dysfunction in a COL4A1 mutant mouse at 9 months. In the present paper, we have analyzed vascular changes in this animal model to better understand the disease physiopathology and investigated retinal cell dysfunction at earlier stages.
ERG was performed to evaluate retinal function on Col4a1 deficient mice. Retinal structure was first examined in vivo using OCT, SLO and Micron III and then on histological sections. Blood vessels were stained on the flat-mounted retina and measured by an automated analysis. Retinal vascular permeability was quantified with the Evans blue dye method. Animals were examined at 3 months and 9 months old.
ERG measurements showed greater cell dysfunction with the animal aging. Mutation in col4a1 was also associated with retinal vessel tortuosity, which was seen only in aging animals confirming thereby age-related changes and vascular reorganization. When the integrity of retinal vessels were examined at 9 months with fluorescence angiography, local area of vascular leakage appeared in different mutant animals but not in control mice. To further investigate this question, Evans blue was perfused in the animal vascular system. This demonstrated the increased albumin vascular leakage in mutant mice with respect to control animals. Finally, we examined retinal vessels at the ultrastructural level and found local thinning of the basement membrane in mutant animals.
This study indicates that the col4a1 deficiency can induce progressive phenotypic retinal features such as retinal cell dysfunction, blood vessel tortuosity, vascular leakage and thinning of the blood basement membrane, all symptoms also observed in diabetic retinopathy. The mouse models may therefore be used to asses further retinal symptoms reported in patients affected by the HANAC syndrome but it could also become an interesting model for vascular retinal pathologies especially diabetic retinopathy.
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