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<p>Diabetic retinopathy (DR) is a leading cause of visual impairment and blindness in industrialized countries, resulting from diabetes mellitus. Prostaglandin E<sub>2</sub> (PGE<sub>2</sub>), synthesized by cyclooxygenases, contributes to inflammation and apoptosis via the E-prostanoid receptor 2 (EP<sub>2</sub>R). Our previous studies demonstrated that EP<sub>2</sub>R antagonists mitigate inflammation and microvascular dysfunction in streptozotocin (STZ)-induced DR. Given the paracrine role of extracellular vesicles (EVs) in DR, we hypothesized that EVs derived from human endothelial cells (ECs) may regulate the PGE<sub>2</sub>/EP<sub>2</sub>R pathway in DR. Using an STZ-induced diabetic mouse model, we administered intravitreal injections of AAV2-shEP<sub>2</sub>R and evaluated retinal histology, optical coherence tomography, and biochemical markers. EV morphology, size, and concentration from high glucose (HG)-treated ECs were analyzed. Small RNA expression in plasma EVs from DR patients was assessed via deep sequencing. EP<sub>2</sub>R inhibition via AAV2-mediated knockdown significantly reduced retinal vascular leakage, leukostasis, and retinal Müller cell (rMC) activation. MiRNA profiling revealed elevated levels of miR-423-5p and miR-21-5p in EVs from HG-treated ECs, which were suppressed in EVs from EP<sub>2</sub>R antagonist-treated cells. Notably, deep sequencing of plasma EVs from DR patients confirmed significant upregulation of these miRNAs compared to healthy controls. MiR-423-5p and miR-21-5p function as key paracrine mediators promoting Müller cell activation and retinal microvascular dysfunction in DR. These findings highlight the potential of circulating EVs as vehicles for miRNA-based therapeutic interventions in DR.</p>

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Endothelial cell-derived microRNAs-containing extracellular vesicles and diabetic retinopathy in a mouse model of diabetes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Meili Wu,
  • Haoyuan Zhou,
  • Tianyi Zong,
  • Ziwen Li,
  • Yujuan Cao,
  • Qian Yang,
  • Tong Mu,
  • Tianhua Xie,
  • Xiaolu Wang,
  • Yong Yao

摘要

Diabetic retinopathy (DR) is a leading cause of visual impairment and blindness in industrialized countries, resulting from diabetes mellitus. Prostaglandin E2 (PGE2), synthesized by cyclooxygenases, contributes to inflammation and apoptosis via the E-prostanoid receptor 2 (EP2R). Our previous studies demonstrated that EP2R antagonists mitigate inflammation and microvascular dysfunction in streptozotocin (STZ)-induced DR. Given the paracrine role of extracellular vesicles (EVs) in DR, we hypothesized that EVs derived from human endothelial cells (ECs) may regulate the PGE2/EP2R pathway in DR. Using an STZ-induced diabetic mouse model, we administered intravitreal injections of AAV2-shEP2R and evaluated retinal histology, optical coherence tomography, and biochemical markers. EV morphology, size, and concentration from high glucose (HG)-treated ECs were analyzed. Small RNA expression in plasma EVs from DR patients was assessed via deep sequencing. EP2R inhibition via AAV2-mediated knockdown significantly reduced retinal vascular leakage, leukostasis, and retinal Müller cell (rMC) activation. MiRNA profiling revealed elevated levels of miR-423-5p and miR-21-5p in EVs from HG-treated ECs, which were suppressed in EVs from EP2R antagonist-treated cells. Notably, deep sequencing of plasma EVs from DR patients confirmed significant upregulation of these miRNAs compared to healthy controls. MiR-423-5p and miR-21-5p function as key paracrine mediators promoting Müller cell activation and retinal microvascular dysfunction in DR. These findings highlight the potential of circulating EVs as vehicles for miRNA-based therapeutic interventions in DR.