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Assessment of Vascular Regeneration in the CNS Using the Mouse Retina
Published on: June 23, 2014
Non-invasive bioelectrical therapy suppresses retinal neovascularization by modulating cellular metabolism and
Anton Lennikov1, Menglu Yang1, Farris Elzaridi1
1Department of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
Background:
Pathological retinal neovascularization, a major cause of blindness, occurs in conditions such as age-related macular degeneration (AMD) and diabetic retinopathy (DR). Microglial activation and chronic neuroinflammation play critical roles in disease progression by promoting vascular permeability and angiogenesis. While anti-VEGF therapies are the current standard of care, their efficacy is limited, requiring frequent intraocular injections and raising concerns about long-term retinal health. Noninvasive transpalpebral electrical stimulation (TpES) has emerged as a potential alternative therapy, but its mechanism and therapeutic impact remain poorly understood.
Methods:
To investigate the therapeutic effects of TpES, we applied daily microcurrent stimulation (300 µA, 20 Hz, 4 min) in laser-induced choroidal neovascularization (CNV) and streptozotocin (STZ)-induced DR mouse models. Vascular pathology was assessed using fluorescein angiography, optical coherence tomography (OCT), and immunohistochemistry. Mechanistic studies were conducted using primary microglia and human retinal endothelial cells (HREC) to evaluate TpES-induced changes in intracellular calcium ([Ca²⁺]i) signaling, mitochondrial membrane potential, and ATP production. Additionally, human RPE/choroidal explants from healthy, AMD, and DR donors were cultured to assess TpES effects on angiogenesis in healthy and pathological human tissues.
Results:
TpES significantly reduced vascular leakage (by ~ 30%, p < 0.001) and lesion size in the CNV model (p < 0.05), while also suppressing microglial infiltration and VEGF-A expression. In the DR model, TpES attenuated microaneurysm formation, preserved endothelial tight junctions (in vitro). Mechanistic studies revealed that TpES suppressed ATP-induced microglial activation by reducing mitochondrial membrane potential and intracellular ATP levels, leading to depletion of ER calcium stores and inhibition of proinflammatory and proangiogenic signaling. TpES also directly suppressed endothelial cell migration and tube formation, as well as angiogenic sprouting in human RPE/choroidal explants.
Conclusions:
These findings establish TpES as a dual-action therapy that mitigates both inflammation and pathological angiogenesis by modulating microglial and endothelial metabolism. Given its noninvasive nature and ability to target key pathways in retinal pathology, TpES represents a promising therapeutic strategy for AMD, DR, and other retinal vascular diseases.
Insights
Transpalpebral electrical stimulation (TpES) offers a novel, noninvasive approach to combat blindness caused by retinal neovascularization. This therapy effectively reduces inflammation and abnormal blood vessel growth in conditions like age-related macular degeneration (AMD) and diabetic retinopathy (DR).
Area of Science:
- Ophthalmology and Neuroscience
- Vascular Biology and Pathology
- Cellular Metabolism and Signaling
Background:
- Pathological retinal neovascularization, a leading cause of blindness in AMD and DR, involves microglial activation and neuroinflammation.
- Current anti-VEGF therapies have limitations, necessitating frequent injections and raising long-term concerns.
- Noninvasive transpalpebral electrical stimulation (TpES) is a potential alternative, but its mechanisms and effects require elucidation.
Purpose of the Study:
- To investigate the therapeutic effects and underlying mechanisms of TpES in preclinical models of retinal neovascularization.
- To assess TpES's impact on vascular leakage, angiogenesis, and neuroinflammation.
- To evaluate TpES's efficacy in both healthy and pathological human retinal tissues.
Main Methods:
- Daily microcurrent stimulation (300 µA, 20 Hz, 4 min) was applied to laser-induced CNV and STZ-induced DR mouse models.
- Vascular pathology was assessed via angiography, OCT, and immunohistochemistry.
- Mechanistic studies involved primary microglia, HRECs, and human RPE/choroidal explants to analyze cellular signaling and metabolic responses to TpES.
Main Results:
- TpES significantly reduced vascular leakage and lesion size in CNV models, suppressing microglial infiltration and VEGF-A.
- In DR models, TpES attenuated microaneurysm formation and preserved endothelial tight junctions.
- Mechanistically, TpES inhibited microglial activation and proangiogenic signaling by modulating mitochondrial function and calcium stores, and directly suppressed endothelial cell migration and angiogenesis.
Conclusions:
- TpES demonstrates a dual therapeutic action, mitigating inflammation and pathological angiogenesis.
- The therapy functions by modulating microglial and endothelial cell metabolism.
- TpES presents a promising, noninvasive therapeutic strategy for AMD, DR, and other retinal vascular diseases.
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