Lina Abdelgabar

Background:  Diabetic retinopathy (DR) is induced by diabetes mellitus complications associated with blood flow dysregulation following chronic hyperglycemia.¹ The retina is highly metabolic, with extensive energy demands; therefore, it is sensitive to changes in blood supply that affect its baseline function, rendering DR a leading cause of vision loss worldwide.¹ DR is categorized into non-proliferative and proliferative stages, with treatments primarily available for the proliferative stages. Currently, early DR stages, where patients are often asymptomatic but pathological changes are already occurring, lack effective therapeutic options¹. Evidence strongly suggests that vasoactive peptides, especially endothelin-1 (ET-1), a potent vasoconstrictor, play a role in microvascular dysfunction that precedes clinical manifestations^2,3. During chronic hyperglycemia, ET-1 becomes dysregulated and promotes retinal vasoconstriction, hypoperfusion, ischemia, and downstream inflammatory injury⁴. Understanding these early mechanisms may reveal novel therapeutic targets to aid in the prevention of irreversible vision loss.

Objective: This narrative review delves into mechanisms underlying the dysregulation of ET-1 signaling in the microvasculature of the retina induced by hyperglycemia. It further examines the contributions of ET-1-mediated microvascular dysfunction to the pathogenesis of early diabetic retinopathy.

Search Methods: A literature search using the PubMed database from 2020 to 2026. Search items included: “diabetic retinopathy,” “endothelin-1,” “retinal vascular dysfunction,” and “hyperglycemia.”

Results: Studies conducted on isolated human and porcine retinal microvessels have demonstrated that ET-1 exerts similar dose-dependent vasoconstrictive effects through the activation of endothelin type A (ET_A) receptors, and high glucose conditions impair endothelium-dependent, nitric oxide (NO)-mediated dilation of these vessels.² ET-1 also elicits significant constriction to ET-1 in porcine and human retinal venules, and this response is enhanced under hyperglycemia without altering resting vascular tone.² This suggests that hyperglycemia sensitizes retinal venules to ET-1 rather than directly causing vasoconstriction. Furthermore, it was revealed that activation of the reverse-mode sodium-calcium exchanger under hyperglycemia leads to an increase in intracellular calcium levels within smooth muscle cells.³ This leads to the amplification of ET-1-induced vasoconstriction, an effect that is attributed to post-receptor signaling rather than the upregulated expression of the ET_A receptor.³ Since the ET-1 level in the retina is elevated under hyperglycemia and elicits retinal arteriolar constriction in the absence of the counteracting effect of NO, this would reduce retinal blood flow, resulting in hypoperfusion and ischemia. The enhanced venular constriction to ET-1 under hyperglycemia elevates capillary pressure, which consequently leads to tissue edema. Ischemic stress activates microglial cells that engage in cross-talk with endothelial cells through the colony-stimulating factor 1 (CSF1/CSF1R) signaling pathway.⁴ This triggers the release of inflammatory cytokines, further exacerbating vascular permeability and microvascular dysfunction. Sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease the expression of ET-1.⁵ Low doses of SGLT2 inhibitors were discovered to mitigate early retinal alterations, including increased thickness, vascular leakage, pericyte loss, and microglial activation, in diabetic mouse models, without affecting blood glucose levels.⁵ Phase II clinical trials investigated a peptide called EG-Mirotin. Subcutaneous administration of this peptide induces platelet integrins to release angiopoietin-1, resulting in substantial reductions in the retinal ischemic index and capillary leakage in patients diagnosed with moderate non-proliferative DR.⁶

Conclusion: In early diabetic retinopathy, ET-1 plays a pivotal role by promoting retinal microvascular constriction, particularly during hyperglycemic states. This constriction leads to a series of retinal hypoperfusion, ischemia, edema, and microvascular inflammation. Potential reversal of these early changes is being explored through the use of SGLT2 inhibitors in preclinical models and EG-Mirotin in clinical trials.

Works Cited:

1. Antonetti DA, Silva PS, Stitt AW. Current understanding of the molecular and cellular pathology of diabetic retinopathy. Nat Rev Endocrinol. 2021;17(4):195-206. doi:10.1038/s41574-020-00451-4
2. Chen YL, Rosa RH Jr, Kuo L, Hein TW. Hyperglycemia augments endothelin-1-induced constriction of human retinal venules. Transl Vis Sci Technol. 2020;9(9):1. 2020 Aug 3. doi:10.1167/tvst.9.9.1
3. Chen YL, Xu W, Rosa RH Jr, Kuo L, Hein TW. Hyperglycemia enhances constriction of retinal venules via activation of the reverse-mode sodium-calcium exchanger. Diabetes. 2019;68(8):1624-1634. doi:10.2337/db19-0069
4. Ben S, Ma Y, Bai Y, et al. Microglia-endothelial cross-talk regulates diabetes-induced retinal vascular dysfunction through remodeling inflammatory microenvironment. iScience. 2024;27(3):109145. Published 2024 Feb 6. doi:10.1016/j.isci.2024.109145
5. Yamato M, Kato N, Yamada KI, Inoguchi T. The Early pathogenesis of diabetic retinopathy and its attenuation by sodium-glucose transporter 2 inhibitors. Diabetes. 2024;73(7):1153-1166. doi:10.2337/db22-0970
6. Yoo S, You DH, Lee J, Hong HC, Lee SJ. A nonrandomized phase 2 trial of EG-Mirotin, a novel, first-in-class, subcutaneously deliverable peptide drug for nonproliferative diabetic retinopathy. Medicina (Kaunas). 2023;59(1):178. Published 2023 Jan 16. doi:10.3390/medicina59010178