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Neurovascular regulation in diabetic retinopathy and emerging therapies

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Abstract

Diabetic retinopathy (DR) is the leading cause of vision loss in working adults in developed countries. The disease traditionally classified as a microvascular complication of diabetes is now widely recognized as a neurovascular disorder resulting from disruption of the retinal neurovascular unit (NVU). The NVU comprising retinal neurons, glia and vascular cells coordinately regulates blood flow, vascular density and permeability to maintain homeostasis. Disturbance of the NVU during DR can lead to vision-threatening clinical manifestations. A limited number of signaling pathways have been identified for intercellular communication within the NVU, including vascular endothelial growth factor (VEGF), the master switch for angiogenesis. VEGF inhibitors are now widely used to treat DR, but their limited efficacy implies that other signaling molecules are involved in the pathogenesis of DR. By applying a novel screening technology called comparative ligandomics, we recently discovered secretogranin III (Scg3) as a unique DR-selective angiogenic and vascular leakage factor with therapeutic potential for DR. This review proposes neuron-derived Scg3 as the first diabetes-selective neurovascular regulator and discusses important features of Scg3 inhibition for next-generation disease-targeted anti-angiogenic therapies of DR.

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Acknowledgements

We would like to thank Dr. Yingbin Fu for scientific discussion. This work was supported by NIH R01EY027749 (WL), R24EY028764 (WL and KAW), R24EY028764-01A1S1 (WL and KAW), R43EY031238 (HT, KAW and WL), R43EY031643 (HT), R41EY027665 (WL and HT), American Diabetes Association 1-18-IBS-172 (WL), NIH P30EY002520, Knights Templar Eye Foundation Endowment in Ophthalmology (WL) and an unrestricted institutional grant from Research to Prevent Blindness (RPB) to Department of Ophthalmology, Baylor College of Medicine.

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Authors and Affiliations

  1. Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, 77030, USA

    Liyang Ji, Keith A. Webster & Wei Li

  2. Department of Ophthalmology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China

    Liyang Ji

  3. Everglades Biopharma, LLC, Houston, TX, 77098, USA

    Hong Tian & Keith A. Webster

  4. Vascular Biology Institute, University of Miami School of Medicine, Miami, FL, 33136, USA

    Keith A. Webster

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  1. Liyang Ji
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All authors were responsible for drafting the article and revising it critically for important intellectual content. All authors approved the version to be published.

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Correspondence to Wei Li.

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HT and WL are shareholders of Everglades Biopharma, LLC and LigandomicsRx, LLC. WL is the inventor of pending patents related to ligandomics and anti-Scg3 therapy.

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Ji, L., Tian, H., Webster, K.A. et al. Neurovascular regulation in diabetic retinopathy and emerging therapies. Cell. Mol. Life Sci. 78, 5977–5985 (2021). https://doi.org/10.1007/s00018-021-03893-9

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