Discovery Suggests New way to Prevent Common Causes of Vision Loss

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FTO in macrophage VEGFA release and choroidal neovascularization. a Quantification of Vegfa, m6A methyltransferase (Mettl3, Mettl4), demethylase (Fto) mRNA levels in pooled eye tissues (n = 3) of control, naive (no laser treated) mice (Ctrl) or mice following laser injury (choroidal neovascularization, CNV, day 3 after laser injury). b, c Immunofluorescent staining of FTO in flat-mounted RPE-choroid tissues (b) and cryosections of eyes (c) at 3 days after laser injury. F4/80 immunostaining indicates macrophage infiltration following laser injury. d, e Immunoblotting and quantification of FTO and F4/80 protein levels in RPE-choroid tissues isolated from mice eyes at 3 days after laser injury (n = 2 eyes). f Immunofluorescent staining of neovascularization using isolectin B4 (green) and of macrophages by F4/80 (red) in RPE-choroid tissues of mice treated with FTO inhibitor (FTOi) or vehicle, at 7 days after laser injury. g, h Quantification of CNV and F4/80 volumes based on isolectin B4 and F4/80 staining in RPE-choroid tissues of mice treated with FTO inhibitor (FTOi) or vehicle, at 7 days after laser injury (n = 24 laser spots for Ctrl, and n = 25 spots for FTOi). i Quantification of VEGFA levels in the RPE/choroid tissues of mice treated with FTO inhibitor (FTOi) or vehicle, at 3 days after laser injury (n = 5 eyes). j Quantification of methylated Vegfa mRNA levels in mouse BMDMs treated with FTO inhibitor (FTOi) or vehicle for 24 h by using MeRIP-qPCR (n = 2). k Determination of Vegfa mRNA stability in BMDMs pretreated with FTO inhibitor (FTOi) or vehicle, followed with Actinomycin D inhibition (10 µg/ml). mRNA abundance was measured by RT-qPCR at the indicated time points and Vegfa mRNA half-lives (t1/2) determined by fitting the data to a nonlinear one phase decay model (mean ± SEM, n = 3). l Schematic diagram showing FTO regulates VEGFA release and choroidal neovascularization in AMD. Retinal pigment epithelium RPE, BM Bruch’s membrane, Mφ macrophages. Data are shown as mean ± SEM, *p < 0.05; ** p < 0.01; ***p < 0.001; ****p < 0.0001; ns not significant. Two-way ANOVA with Sidak’s multiple comparisons (a, c); One-way analysis of variance (ANOVA) with Dunnett’s multiple comparisons (g); unpaired two-tailed t-test (e, j, g, k). Credit: Signal Transduction and Targeted Therapy (2023). DOI: 10.1038/s41392-022-01277-4

UVA Health scientists have discovered an unknown contributor to harmful blood vessel growth in the eye that could lead to new treatments for blinding macular degeneration and other common causes of vision loss.

UVA's Jayakrishna Ambati, MD, and Shao-bin Wang, Ph.D., and their colleagues have identified a new target to prevent the formation of abnormal tangles of blood vessels associated with eye conditions such as neovascular age-related macular degeneration, proliferative diabetic retinopathy and ischemic retinal vein occlusion.

"Our study has opened up the possibility of mitigating aberrant blood vessel growth in eye diseases by targeting the epigenetic machinery," said Ambati, the founding director of UVA's Center for Advanced Vision Science and a member of the University of Virginia School of Medicine's Department of Ophthalmology.

"Through local targeting of the epigenetic regulator, we have gained a deeper understanding of how ocular immune cells can cause a loss of control over blood vessel growth under the retina. This approach also offers a new direction for the development of more effective, cost-efficient and accessible interventions, thereby avoiding issues such as drug resistance, which is a growing concern with conventional anti-VEGF therapies used in clinical treatments."

Understanding vision loss

Scientists have known that abnormal vessel overgrowth in the eye is fueled by excessive amounts of a substance called "vascular endothelial growth factor-A," or VEGF, that plays an important role in blood vessel formation. There are now treatments available that target VEGF to prevent vessel overgrowth, and they often provide dramatic benefits at first. Unfortunately, these benefits can fade with time. That leaves doctors in need of better treatments to help preserve patients' eyesight.

Ambati and Wang's new research identifies a key protein that determines VEGF levels. Blocking this protein in lab mice reduced their VEGF levels significantly, and it did so in a targeted way, without unwanted side effects. The scientists noted, for example, that they observed no toxic effects on the retina, the light-sensing portion of the eye where the vessel overgrowth occurs.

"This fat mass and obesity-associated (FTO) protein was previously shown to be correlated with obesity in humans. Unexpectedly, we found it also play important roles in regulating ocular neovascularization through an epigenetic mechanism," Ambati said. "This exciting discovery finally answers a longstanding question about how ocular immune cells, such as macrophages, contribute to abnormal blood vessel growth under the retina. This question was first investigated by our team 20 years ago, and we're thrilled to have found an answer."

In addition to identifying a promising target for the development of new treatments for vision loss, the discovery sheds important light on the fundamental mechanisms responsible for the blood vessel overgrowth that robs millions of people of their sight. Neurovascular age-related macular degeneration alone affects more than 200 million people worldwide. While much more research and testing will be needed before the new finding could be translated into a treatment, the UVA scientists are excited about the potential of the discovery.

"Current strategies for treating ocular neovascular disorders, which primarily focus on regulating the protein levels of VEGF, are not perfect. Therefore, it is imperative to identify more targetable candidates to develop alternative therapies," Wang said. "We are hopeful that our study will pave the way for the development of new treatments, ultimately reducing the burden of neovascular-related illnesses."

The researchers have published their findings in Signal Transduction and Targeted Therapy.

More information: Shao-bin Wang et al, Targeting the m6A mRNA demethylase FTO suppresses vascular endothelial growth factor release and choroidal neovascularization, Signal Transduction and Targeted Therapy (2023). DOI: 10.1038/s41392-022-01277-4

Citation: Discovery suggests new way to prevent common causes of vision loss (2023, February 24) retrieved 24 February 2023 from

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