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Glutamatergic neuronal activity regulates retinal angiogenesis and blood-retinal barrier via Norrin/b-catenin signaling

ABSTRACT: Glutamatergic neuronal activity regulates retinal angiogenesis and blood-retinal barrier via Norrin/b-catenin signaling

PROVIDER: PRJNA988140 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25041747_1.fastq.gz	Fastqsanger.gz
	SRR25041747_2.fastq.gz	Fastqsanger.gz
	SRR25041748_1.fastq.gz	Fastqsanger.gz
	SRR25041748_2.fastq.gz	Fastqsanger.gz
	SRR25041749_1.fastq.gz	Fastqsanger.gz

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Glutamatergic neuronal activity regulates retinal angiogenesis and blood-retinal barrier via Norrin/b-catenin signaling

Project description:Interactions among neuroglial and vascular components are crucial for retinal angiogenesis and blood-retinal barrier (BRB) maturation. Neuronal synaptic dysfunctions precede vascular abnormalities in many retinal pathologies. However, whether neuronal activity, specifically glutamatergic activity, regulates retinal angiogenesis and BRB maturation remains unclear. Using in vivo genetic studies in mice, single-cell RNA-sequencing and functional validation, we found that deep plexus angiogenesis and paracellular BRB maturation are delayed in Vglut1-/- retinas, where neurons fail to release glutamate. In contrast, deep plexus angiogenesis and paracellular BRB maturation are accelerated in Gnat1-/- retinas, where constitutively depolarized rods release excess glutamate. Mechanistically, Norrin expression and endothelial Norrin/b-catenin signaling are downregulated in Vglut1-/- retinas, and upregulated in Gnat1-/- retinas. Pharmacological activation of endothelial Norrin/ b-catenin signaling in Vglut1-/- retinas rescued both deep plexus angiogenesis and paracellular BRB integrity. Thus, our findings demonstrate that glutamatergic neuronal activity regulates retinal angiogenesis and BRB maturation by modulating Norrin/b-catenin signaling.

2024-06-27 | GSE235993 | GEO

Therapeutic modulation of the blood-brain barrier and ischemic stroke by a bioengineered FZD4-selective WNT surrogate

Project description:Derangements of the blood-brain barrier (BBB) or blood-retinal barrier (BRB) occur in disorders ranging from stroke, cancer, diabetic retinopathy, and Alzheimer's disease. The Norrin/FZD4/TSPAN12 pathway activates WNT/-catenin signaling, which is essential for BBB and BRB function. However, systemic pharmacologic FZD4 stimulation is hindered by obligate palmitoylation and insolubility of native WNTs and suboptimal properties of the FZD4-selective ligand Norrin. Here, we developed L6-F4-2, a non-lipidated, FZD4-specific surrogate with significantly improved sub-picomolar affinity versus native Norrin. In Norrin knockout (NdpKO) mice, L6-F4-2 not only potently reversed neonatal retinal angiogenesis deficits, but also restored BRB and BBB function. In adult C57Bl/6J mice, post-stroke systemic delivery of L6-F4-2 strongly reduced BBB permeability, infarction, and edema, while improving neurologic score and capillary pericyte coverage. Our findings reveal systemic efficacy of a bioengineered FZD4-selective WNT surrogate during ischemic BBB dysfunction, with general applicability to adult CNS disorders characterized by an aberrant blood-brain barrier.

2023-01-31 | GSE223498 | GEO

Therapeutic modulation of the blood-brain barrier and ischemic stroke by a bioengineered FZD4-selective WNT surrogate (bulk)

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FOXC1 regulates endothelial CD98 (LAT1/4F2hc) expression in retinal angiogenesis and blood-retina barrier formation

Project description:Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is essential for the development of new organ systems, but transcriptional control of angiogenesis remains incompletely understood. Here we report that FOXC1 is essential for retinal angiogenesis. Endothelial cell (EC)-specific loss of Foxc1 impairs retinal vascular growth and expression of Slc3a2 and Slc7a5, which encode the heterodimeric CD98 (LAT1/4F2hc) amino acid transporter and regulate the intracellular transport of essential amino acids and activation of the mammalian target of rapamycin (mTOR). EC-Foxc1 deficiency diminishes mTOR activity, while administration of the mTOR agonist MHY-1485 rescues perturbed retinal angiogenesis. EC-Foxc1 expression is required for retinal revascularization and resolution of neovascular tufts in a model of oxygen-induced retinopathy. Foxc1 is also indispensable for pericytes, a critical component of the blood-retina barrier during retinal angiogenesis. Our findings establish FOXC1 as a crucial regulator of retinal vessels and identify therapeutic targets for treating retinal vascular disease.

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Transcriptional response to Frizzled4 signaling in cultured retinal endothelial cells

Project description:Transcriptional profiles of Fz4-/- retinal endothelial cells were compared to that of wild type endothelial cells under various culture conditions. The goal was to identify the transcriptional response to Frizzled 4 signaling in cultured retinal endothelial cells. To analyze the Norrin response of WT and Fz4-/- retinal endothelial cells in culture, we co-cultured these cells either with HEK293 cell line that stably expresses Norrin or with control 293 cells.

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Transcription profiling of mouse cultured retinal endothelial cells - regulation by Norrin-Frizzled4 signaling (Super Series)

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Role of microRNA-143, -150 and 126 in pathological retinal angiogenesis

Project description:Retinal neovascularization is a severe complication of proliferative diabetic retinopathy. We have previously identified that miRNAs is directly involved in the development of retinal neovascularization. Here, we explored the role of miRNAs and its underlying mechanism in modulating angiogenesis.

2021-10-01 | GSE139947 | GEO

Comparative analysis of Retinal Angiogenesis during Inflammatory stage

Project description:Comparative analysis of Retinal Angiogenesis during Inflammatory stage

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Transcription profiling of mouse decrement in Norrin/Frizzled4/Lrp signaling in retinal endothelial cells

Project description:To characterize the long-term effect on the transcriptome of a decrement in Norrin/Fz4/Lrp signaling, microarray hybridization was performed with RNA from acutely dissociated and anti-PECAM immunoaffinity-purified adult WT, Fz4-/-, Lrp5-/-, and Norrin- retinal vascular cells. Experiment Overall Design: Retinal endothelial cells from 5-10 adult mice were pooled for each sample, the cell immuno-purification procedure follows that described by Matsubara et al. (2000) and Su et al. (2003). 3 replicates of each mutant and 6 replicates of control wild type animals were analyzed.

2009-10-10 | E-GEOD-16703 | biostudies-arrayexpress

Long-term effect on the transcriptome of a decrement in Norrin/Frizzled4/Lrp signaling in retinal endothelial cells

2009-10-01 | GSE16703 | GEO