Novel Study Uncovers the Critical Role of ADAM10 Protein in the Development of Retinal Disorders

New research has found that the endothelial cell-specific A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) regulates abnormal blood vessel growth in the damaged retina, which can cause vision loss or impairment. The findings of the new studyopens in new tab/window in The American Journal of Pathologyopens in new tab/window, published by Elsevier, have significant implications for understanding the pathophysiology of neovascular disorders like retinopathy of prematurity and diabetic retinopathy and provide a potential target for treatment.

ADAM10, a versatile protein involved in a wide range of cellular processes, particularly those related to the regulation of cell surface protein expression and intercellular communication, is known to have a physiological role in normal blood vessel formation. However, its role in proliferative retinopathies, in which abnormal blood vessel formation is the primary cause of vision loss and impairment, remains understudied.

The present study explored the role of endothelial cell-specific ADAM10 and its signaling on pathologic neovascularization within the retina. Using an endothelial-specific ADAM10 knockout mouse model (ADAM10^i∆EC), its goal was to uncover the molecular mechanisms underpinning ADAM10 participation in retinal neovascularization to provide fresh insights into potential therapeutic targets for retinal neovascular disorders.

Lead investigator Nikhlesh K. Singh, DVM, PhD, Integrative Biosciences Center and Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, says, “In this study, we discovered that ADAM10 activity was significantly elevated in the injured retina, and reducing ADAM10 levels or its activity notably slowed the growth, spread, movement, and tube formation of human retinal microvascular endothelial cells. Additionally, when we eliminated ADAM10 from the endothelial cells in mice, it substantially alleviated issues associated with retinal diseases, such as blood leakage from vessels, swelling, and the formation of new blood vessels.”

While investigating how ADAM10 influences abnormal blood vessel growth, the researchers found that ADAM10 regulates the levels of the protein Ephrin B2 in endothelial cells, and decreasing Ephrin B2 levels impacts the growth, movement, sprouting, and tube formation of human retinal endothelial cells. Furthermore, a significant increase in Ephrin B2 expression was observed in the damaged retina, and the removal of ADAM10 specifically from endothelial cells drastically reduced Ephrin B2 expression, indicating that ADAM10 plays a crucial role in the development of new blood vessels in the retina by regulating Ephrin B2 levels.

Pathologic retinal neovascularization is the primary cause of visual loss in diseases such as proliferative diabetic retinopathy, retinopathy of prematurity, central vein occlusion, and age-related macular degeneration. The extracellular matrix breakdown by metalloproteinase leads to vascular complications in various proliferative retinopathies. Most of the current therapeutic approaches for these diseases involve invasive and moderately effective surgical procedures, such as anti-VEGF (Vascular Endothelial Growth Factor) treatment.

Co-investigators Shivantika Bisen, MSc, and Purnima Gogoi, PhD, MVSc, Integrative Biosciences Center and Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, and Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin (PG), note, “Various clinical and experimental findings report that the use of anti-VEGF agents can result in neuronal damage, hypertension, myocardial infarction, stroke, and diabetes. Additionally, there are many patients who do not respond to anti-VEGF therapies. Our study shows that targeting ADAM10 or its downstream effectors, such as Ephrin B2, could offer novel strategies for managing or preventing retinal diseases characterized by pathologic neovascularization.”

Dr. Singh concludes, “The human body is a sophisticated and autonomous system, and we, as medical researchers, strive to comprehend the intricacies of its existence and functionality, continually fascinated by its self-sufficiency and resilience. Our study has significant implications for understanding the pathophysiology of hypoxic and/or ischemic retinal diseases and highlights potential therapeutic targets, paving the way for novel treatment strategies beyond current anti-VEGF therapies.”

Notes for editors

The article is “A Disintegrin and Metalloproteinase 10 Regulates Ephrin B2–Mediated Endothelial Cell Sprouting and Ischemic Retinopathy,” by Shivantika Bisen, Purnima Gogoi, Anamika Sharma, Chandra S. Mukhopadhyay, and Nikhlesh K. Singh (https://doi-org.ucc.idm.oclc.org/10.1016/j.ajpath.2025.03.007opens in new tab/window). It appears in The American Journal of Pathology, volume 195, issue 7 (July 2025), published by Elsevier.

The article is openly available for 90 days at https://ajp.amjpathol.org/article/S0002-9440(25)00114-2/fulltextopens in new tab/window.

Full text of the article is also available to credentialed journalists upon request. Contact Eileen Leahy at +1 732 406 1313 or [email protected]opens in new tab/window to request a PDF of the article or more information. To reach the study’s authors, contact Julie O'Connor, Director of Research Communications, Division of Research & Innovation, Wayne State University, at +1 313 577 8845 or [email protected]opens in new tab/window.

The study was supported by National Institutes of Health, National Eye Institute, EY029709 and P30EY04068, and a Research to Prevent Blindness unrestricted grant (Kresge Eye Institute).

About The American Journal of Pathology

The American Journal of Pathologyopens in new tab/window, official journal of the American Society for Investigative Pathologyopens in new tab/window, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. ajp.amjpathol.orgopens in new tab/window

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