Evidence map›Paper›PMID 41199318›Full record

ArticleCell communication and signaling : CCS2025

Non-invasive bioelectrical therapy suppresses retinal neovascularization by modulating cellular metabolism and inflammation.

Anton Lennikov, Menglu Yang, Farris Elzaridi, Daisy Y Shu, Zhengping Hu, William P Miller, Matthijs Tsonas, Lu Huang, Christina Yen, Karen Chang and 7 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell communication and signaling : CCS, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
  2. Article
  3. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Anton LennikovDepartment of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
Menglu YangDepartment of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
Farris ElzaridiDepartment of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
Daisy Y ShuDepartment of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
Zhengping HuDepartment of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
William P MillerDepartment of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
Matthijs TsonasDepartment of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
Lu HuangDepartment of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
Christina YenDepartment of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
Karen ChangDepartment of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
Julie ChenDepartment of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
Aruvi VijikumarDepartment of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
Ajay AshokDepartment of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
Kin-Sang ChoDepartment of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
Magali Saint GeniezDepartment of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
Darlene A DarttDepartment of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
Dong Feng ChenDepartment of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA. Dongfeng_chen@meei.harvard.edu.

Funding

Conjunctival Goblet Cell Mucin Secretion in Inflammation and Its ResolutionR01EY019470 · NEI · SCHEPENS EYE RESEARCH INSTITUTE · PI DARTT, DARLENE A · 2009 to 2023
$7.4M
Innate and Adaptive Immunity in the Pathogenesis of GlaucomaR01EY031696 · NEI · SCHEPENS EYE RESEARCH INSTITUTE · PI Dong Feng Chen, Jianzhu Chen · 2021 to 2026
$5.2M
BrightFocus Foundation M2021010FNEI NIH HHS R01 EY019470NEI NIH HHS R01EY019470NEI NIH HHS R01 EY031696NEI NIH HHS R01EY031696U.S. Department of Defense HT9425-23-1-1045U.S. Department of Defense HT9425-24-1-0788
6 · The paper itself

Abstract

backgroundPathological 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.

methodsTo 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.

resultsTpES 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.

conclusionsThese 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.

Indexed as

Electric Stimulation TherapyInflammationRetinal NeovascularizationAdenosine TriphosphateAnimalsChoroidal NeovascularizationDiabetic RetinopathyEndothelial CellsHumansMaleMembrane Potential, MitochondrialMiceMice, Inbred C57BLMicrogliaRetinaAdenosine TriphosphateAngiogenesisCa2+ signalingElectrical stimulationMicrogliaMitochondriaRetinal endothelial cells

Identifiers

PMID41199318
PMCPMC12590768

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.