Breakdown of the blood-retinal barrier (BRB) causes retinal edema and vision loss. We investigated the role of Wnt signaling in maintaining the BRB by limiting transcytosis. Mice lacking either the Wnt co-receptor low-density lipoprotein receptor–related protein 5 (Lrp5^−/−) or the Wnt ligand Norrin (Ndp^y/−) exhibit increased retinal vascular leakage and enhanced endothelial transcytosis. Wnt signaling directly controls the transcription of an endothelium-specific transcytosis inhibitor, major facilitator superfamily domain–containing protein 2a (MFSD2A), in a β-catenin–dependent manner. MFSD2A overexpression reverses Wnt deficiency–induced transcytosis in endothelial cells and in retinas. Moreover, Wnt signaling mediates MFSD2A-dependent vascular endothelium transcytosis through a caveolin-1 (CAV-1)–positive caveolae pathway. In addition, levels of omega-3 fatty acids are also decreased in Wnt signaling–deficient retinas, reflecting the basic function of MFSD2A as a lipid transporter. Our findings uncovered the Wnt/β-catenin/MFSD2A/CAV-1 axis as a key pathway governing endothelium transcytosis and inner BRB integrity.

Diabetic retinopathy (DR) is a complication of diabetes and one of the leading causes of vision loss worldwide. Despite extensive efforts to reduce visual impairment, the prevalence of DR is still increasing. The initial pathophysiology of DR includes damage to vascular endothelial cells and loss of pericytes. Ensuing hypoxic responses trigger the expression of vascular endothelial growth factor (VEGF) and other pro-angiogenic factors. At present, the most effective treatment for DR and diabetic macular edema (DME) is the control of blood glucose levels. More advanced cases require laser, anti-VEGF therapy, steroid, and vitrectomy. Pan-retinal photocoagulation for non-proliferative diabetic retinopathy (NPDR) is well established and has demonstrated promising outcomes for preventing the progressive stage of DR. Furthermore, the efficacy of laser therapies such as grid and subthreshold diode laser micropulse photocoagulation (SDM) for DME has been reported. Vitrectomy has been performed for vitreous hemorrhage and tractional retinal detachment for patients with PDR. In addition, anti-VEGF treatment has been widely used for DME, and recently its potential to prevent the progression of PDR has been remarked. Even with these treatments, many patients with DR lose their vision and suffer from potential side effects. Thus, we need alternative treatments to address these limitations. In recent years, the relationship between DR, lipid metabolism, and inflammation has been featured. Research in diabetic animal models points to peroxisome proliferator-activated receptor alpha (PPARα) activation in cellular metabolism and inflammation by oral fenofibrate and/or pemafibrate as a promising target for DR. In this paper, we review the status of existing therapies, summarize PPARα activation therapies for DR, and discuss their potentials as promising DR treatments.

The light‐sensitive photoreceptors in the retina are extremely metabolically demanding and have the highest density of mitochondria of any cell in the body. Both physiological and pathological retinal vascular growth and regression are controlled by photoreceptor energy demands. It is critical to understand the energy demands of photoreceptors and fuel sources supplying them to understand neurovascular diseases. Retinas are very rich in lipids, which are continuously recycled as lipid‐rich photoreceptor outer segments are shed and reformed and dietary intake of lipids modulates retinal lipid composition. Lipids (as well as glucose) are fuel substrates for photoreceptor mitochondria. Dyslipidemia contributes to the development and progression of retinal dysfunction in many eye diseases. Here, we review photoreceptor energy demands with a focus on lipid metabolism in retinal neurovascular disorders.

Photoreceptor degeneration caused by genetic defects leads to retinitis pigmentosa, a rare disease typically diagnosed in adolescents and young adults. In most cases, rod loss occurs first, followed by cone loss as well as altered function in cells connected to photoreceptors directly or indirectly. There remains a gap in our understanding of retinal cellular responses to photoreceptor abnormalities. Here, we utilized single-cell transcriptomics to investigate cellular responses in each major retinal cell type in retinitis pigmentosa model (P23H) mice vs. wild-type littermate mice. We found a significant decrease in the expression of genes associated with phototransduction, the inner/outer segment, photoreceptor cell cilium, and photoreceptor development in both rod and cone clusters, in line with the structural changes seen with immunohistochemistry. Accompanying this loss was a significant decrease in the expression of genes involved in metabolic pathways and energy production in both rods and cones. We found that in the Müller glia/astrocyte cluster, there was a significant increase in gene expression in pathways involving photoreceptor maintenance, while concomitant decreases were observed in rods and cones. Additionally, the expression of genes involved in mitochondrial localization and transport was increased in the Müller glia/astrocyte cluster. The Müller glial compensatory increase in the expression of genes downregulated in photoreceptors suggests that Müller glia adapt their transcriptome to support photoreceptors and could be thought of as general therapeutic targets to protect against retinal degeneration.

Large-scale clinical trials, such as the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies, have shown that the administration of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, suppresses the progression of diabetic retinopathy. In this paper, we reveal a therapeutic effect of a selective PPARα modulator (SPPARMα), pemafibrate, against pathological angiogenesis in murine models of retinopathy. Oxygen-induced retinopathy (OIR) was induced in C57BL/6J mice by exposure to 85% oxygen from postnatal day eight (P8) for 72 h. Vehicle, pemafibrate or fenofibrate was administrated by oral gavage from P12 to P16 daily. Administration of pemafibrate, but not fenofibrate, significantly reduced pathological angiogenesis in OIR. After oral pemafibrate administration, expression levels of downstream PPARα targets such as acyl-CoA oxidase 1 (Acox1), fatty acid binding protein 4 (Fabp4), and fibroblast growth factor 21 (Fgf21) were significantly increased in the liver but not in the retina. A significant increase in plasma FGF21 and reduced retinal hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (Vegfa) were also observed after this treatment. In an in vitro HIF-luciferase assay, a long-acting FGF21 analogue, but not pemafibrate, suppressed HIF activity. These data indicate that SPPARMα pemafibrate administration may prevent retinal pathological neovascularization by upregulating FGF21 in the liver.