Non-invasive real-time pulsed Doppler assessment of blood flow in mouse ophthalmic artery

Cell Reports Methods, Journal Year: 2025, Volume and Issue: unknown, P. 100983 - 100983

Published: Feb. 1, 2025

Non-invasive and high-temporal resolution methods for characterizing blood flow in mouse cranial arteries, such as the ophthalmic artery (OphA), are lacking. We present an application of pulsed Doppler ultrasound to provide real-time, non-invasive measurement velocity OphA through identified soft tissue window head. confirmed identity mapped its origin from internal carotid by a combination microcomputed tomography (microCT) vascular imaging transient occlusion artery. Application our approach demonstrated sex differences vasodilative response agonists. also evaluated real-time characteristics ligation. The method will simple low-cost screening drugs targeting can be used more accessible surrogate cerebral both acute longitudinal studies.

Language: Английский

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Intracameral Puncture Lowers Intraocular Pressure and Triggers an Immune Response in the Conventional Outflow Tract

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Intracameral injection is an effective delivery method for biomedical agents and therapeutics to conventional outflow tract tissues. However, the effect of intracameral injections on intraocular pressure aqueous dynamics has not been well characterized, warranting further investigation. Wild type 3-5-month-old C57BL/6 mice were subjected puncture (ICP, without any material). Following ICP, (IOP), facility, production, episcleral vessel diameter, macrophage densities measured. On day 1, IOP was significantly reduced by 30% ( p < 0.0001; n=25) while facility = 0.306; n=15) production 0.163; n=9) unchanged. As well, Schlemm's canal filtration area unchanged, however distal vessels dilated 0.001) at 1 post ICP. Correspondingly, density increased around 0.0005) 1. Macrophage in trabecular meshwork, unchanged 3 0.0001). Coincident with one after there influx macrophages into portion tissues a dilation vessels, likely reducing resistance. Our study demonstrates importance considering drug eye due its effects immune response homeostasis.

Language: Английский

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TGFβ2 alters segmental outflow and ECM ultrastructure in the trabecular meshwork

Experimental Eye Research, Journal Year: 2025, Volume and Issue: 255, P. 110377 - 110377

Published: April 10, 2025

Language: Английский

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Magnetically steered cell therapy for reduction of intraocular pressure as a treatment strategy for open-angle glaucoma

Published: May 7, 2025

Trabecular meshwork (TM) cell therapy has been proposed as a next-generation treatment for elevated intraocular pressure (IOP) in glaucoma, the most common cause of irreversible blindness. Using magnetic steering technique with excellent efficiency and tissue-specific targeting, we delivered two types cells into mouse model glaucoma: either human adipose-derived mesenchymal stem (hAMSCs) or induced pluripotent derivatives (iPSC-TM cells). We observed 4.5 [3.1, 6.0] mmHg 27% reduction nine months after single dose only 1500 magnetically-steered hAMSCs, explained by increased outflow through conventional pathway associated an higher TM cellularity. iPSC-TM were also effective, but less so, showing 1.9 [0.4, 3.3] 13% IOP risk tumorigenicity. In both cases, injected remained detectable iridocorneal angle three weeks post-transplantation. Based on locations cells, mechanism lowering is likely paracrine signaling. conclude that hAMSC potential long-term ocular hypertension glaucoma.

Language: Английский

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Fibronectin extra domain A (FN-EDA) causes glaucomatous trabecular meshwork, retina, and optic nerve damage in mice

Cell & Bioscience, Journal Year: 2022, Volume and Issue: 12(1)

Published: May 26, 2022

Abstract Background Elevated intraocular pressure (IOP) is a major risk factor for the development and progression of primary open angle glaucoma due to trabecular meshwork (TM) damage. Here, we investigate role an endogenous Toll-like receptor 4 (TLR4) ligand, FN-EDA, in utilizing transgenic mouse strain (B6.EDA +/+ ) that constitutively expresses only FN containing EDA isoform. Methods Eyes from C57BL6/J (wild-type), B6.EDA+/+ (constitutively active EDA), B6.EDA-/- (EDA null) mice were processed electron microscopy consecutive images entire length TM Schlemm’s canal (SC) anterior posterior collected montaged into single image. ECM accumulation, basement membrane length, size number giant vacuoles quantified by ImageJ analysis. Tlr4 Iba1 expression ONH cells was conducted using RNAscope situ hybridization immunohistochemistry protocols. IOP measured rebound tonometer, ON damage assessed PPD stain, RGC loss RBPMS labeled retina flat mounts. Results Ultrastructure analyses show B6.EDA have significantly increased accumulation between beams with few empty spaces compared C57BL/6 J (p < 0.05). SC thicker more continuous J. No significant structural differences are detected null mice. eyes higher 0.001), 0.001) 0.05) at 1 year age. mRNA expressed cells, present ganglion cell axons, microglia, astrocytes. There increase area occupied Iba-1 positive microglia control 0.01). Conclusions TM, elevated IOP, enhanced proinflammatory changes ONH, RGCs, These data suggest recapitulate many aspects glaucomatous

Language: Английский

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TGFβ Signaling Dysregulation May Contribute to COL4A1-Related Glaucomatous Optic Nerve Damage

Investigative Ophthalmology & Visual Science, Journal Year: 2024, Volume and Issue: 65(5), P. 15 - 15

Published: May 8, 2024

Purpose: Mutations in the genes encoding type IV collagen alpha 1 (COL4A1) and 2 (COL4A2) cause a multisystem disorder that includes ocular anterior segment dysgenesis (ASD) glaucoma. We previously showed transforming growth factor beta (TGFβ) signaling was elevated developing segments from Col4a1 mutant mice reducing TGFβ ameliorated ASD, supporting role for pathway disease pathogenesis. Here, we tested whether altered also contributes to glaucoma-related phenotypes mice. Methods: To test of glaucoma-relevant phenotypes, genetically reduced using with mutated Tgfbr2, which encodes common receptor all ligands Col4a1+/G1344D performed slit-lamp biomicroscopy optical coherence tomography qualitative quantitative analyses posterior segments, histological tissues optic nerves, intraocular pressure assessments rebound tonometry. Results: defects drainage structures, including iridocorneal adhesions, consistent glaucomatous neurodegeneration, thinning nerve fiber layer, retinal ganglion cell loss, head excavation, degeneration. found (TGFBR2) protective structure defects, protected against neurodegeneration Conclusions: Our results suggest

Language: Английский

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Human Pro370Leu Mutant Myocilin Induces the Phenotype of Open-Angle Glaucoma in Transgenic Mice

Cellular and Molecular Neurobiology, Journal Year: 2022, Volume and Issue: 43(5), P. 2021 - 2033

Published: Sept. 7, 2022

Language: Английский

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Modeling the biomechanics of the conventional aqueous outflow pathway microstructure in the human eye

Computer Methods and Programs in Biomedicine, Journal Year: 2022, Volume and Issue: 221, P. 106922 - 106922

Published: May 29, 2022

Language: Английский

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Neuroprotective Effects of Transferrin in Experimental Glaucoma Models

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(21), P. 12753 - 12753

Published: Oct. 22, 2022

Iron is essential for retinal metabolism, but an excess of ferrous iron causes oxidative stress. In glaucomatous eyes, ganglion cell (RGC) death has been associated with dysregulation homeostasis. Transferrin (TF) endogenous transporter that controls ocular levels. Intraocular administration TF neuroprotective in various models degeneration, preventing overload and reducing iron-induced Herein, we assessed the protective effects on RGC survival, using ex vivo rat explants exposed to iron, NMDA-induced excitotoxicity, or CoCl2-induced hypoxia, model hypertension (OHT). significantly preserved RGCs against FeSO4-induced toxicity, hypoxia. protected from apoptosis, ferroptosis, necrosis. OHT rats, reduced loss by about 70% compared vehicle-treated animals 47% axons. Finally, increased staining was shown retina a glaucoma patient's eye as non-glaucomatous eyes. These results indicate can interfere different cell-death mechanisms involved pathogenesis demonstrate ability protect elevated IOP. Altogether, these suggest promising treatment neuropathy.

Language: Английский

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Macrophage-induced integrin signaling promotes Schlemm’s canal formation to prevent intraocular hypertension and glaucomatous optic neuropathy

Cell Reports, Journal Year: 2024, Volume and Issue: 43(2), P. 113799 - 113799

Published: Feb. 1, 2024

Schlemm's canal (SC) functions to maintain proper intraocular pressure (IOP) by draining aqueous humor and has emerged as a promising therapeutic target for glaucoma, the second-leading cause of irreversible blindness worldwide. However, our current understanding mechanisms governing SC development functionality remains limited. Here, we show that vitronectin (VTN) produced limbal macrophages promotes formation prevents hypertension activating integrin αvβ3 signaling. Genetic inactivation this signaling system inhibited phosphorylation AKT FOXO1 reduced β-catenin activity FOXC2 expression, thereby causing impaired Prox1 expression deteriorated morphogenesis. This ultimately led increased IOP glaucomatous optic neuropathy. Intriguingly, found aged displayed downregulated β3 in association with dampened expression. Conversely, inhibition rejuvenated inducing regrowth, highlighting possible strategy targeting VTN/integrin improve functionality.

Language: Английский

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