Abstract
Purpose :
Genome-wide association studies have linked the 677C>T variant within the MTHFR gene with both glaucoma and central retinal vein occlusion. Presence of the variant results in a 50% reduction in MTHFR enzyme activity and a significant increase in levels of plasma homocysteine which promotes vascular dysfunction. We utilize a mouse model carrying Mthfr677C>T to assess variant-specific retinal vascular and RGC damage following acute ocular hypertension.
Methods :
To induce ocular hypertension, we use a photopolymerizable biomatrix, hyaluronic acid glycidyl methacrylate (HAMA). This allows for in vivo crosslinking of the biomatrix at the iridocorneal angle by exposure to UVA light to block the aqueous outflow. IOP elevation can be maintained at ~45% above baseline for up to 4 weeks after one injection. In vivo, pattern electroretinography (PERG) and fluorescence angiography (FA) will be performed to assess RGC function and vascular deficits, respectively, at baseline and 3-4 weeks post-HAMA in young (6 month) and aged (18 month) control and Mthfr677C>T mice. Ex vivo, RGC counts and known markers for vascular damage will be assessed.
Results :
Mice carrying the 677C>T variant present with baseline vascular deficits by 6 months of age, including reduced vessel density, decreased arteriole diameter, and increased vessel tortuosity in addition to altered microglial-vessel interactions. In vivo FA shows a reduction of blood flow with age. While RGC numbers are not different at baseline between genotypes, counts following HAMA are currently being evaluated.
Conclusions :
Vascular dysfunction in glaucoma is a less studied, but important contributor to initiation and progression of the disease. Here, we examine a new mouse model with a clinically relevant risk variant in order to assess susceptibility to a hypertensive insult.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.