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Background <p>Diabetic retinopathy (DR) is a major cause of vision loss, driven by endothelial dysfunction and endothelial-to-mesenchymal transition (EndoMT). Caveolae and associated proteins like caveolin-2 (CAV2), crucial for vascular homeostasis, may contribute to DR pathogenesis. This study explores the role of CAV2 and its downstream mediator plasminogen activator inhibitor-1 (PAI-1) in retinal vascular damage and EndoMT during DR.</p> Methods <p>Transcriptomic profiles of CD31⁺ endothelial cells from fibrovascular membranes of patients with proliferative diabetic retinopathy were analyzed using the GSE94019 dataset to identify differentially expressed caveolae-associated genes. Streptozotocin (STZ)-induced DR was established in C57BL/6J mice, including endothelial-specific CAV2 knockout (<sup>Endo</sup>CAV2<sup>KO</sup>) mice generated by breeding CAV2<sup>fl/fl</sup> with Cdh5-Cre mice. Adeno-associated virus (AAV) vectors were used to overexpress CAV2 or knock down PAI-1. CAV2, CD31, α-smooth muscle actin (α-SMA), vimentin, and PAI-1 expression were assessed via RT-qPCR, Western blot, and immunofluorescence. Retinal structure and vascular permeability were evaluated by hematoxylin–eosin staining and Evans blue assay, respectively. Statistical comparisons were performed using Student's t-test or ANOVA with Tukey's post-hoc test.</p> Results <p>Transcriptomic analysis revealed CAV2 downregulation in DR endothelial cells, which was confirmed by reduced CAV2 mRNA and protein levels in retinas of STZ-treated mice. Immunofluorescence demonstrated decreased CAV2 expression specifically in CD31⁺ retinal endothelial cells of diabetic mice. Endothelial CAV2 overexpression attenuated EndoMT, preserved retinal thickness, and decreased vascular permeability. Conversely, <sup>Endo</sup>CAV2<sup>KO</sup> mice exhibited exacerbated retinal damage, vascular leakage, and EndoMT, accompanied by elevated PAI-1 levels. PAI-1 knockdown in <sup>Endo</sup>CAV2<sup>KO</sup> mice alleviated these pathological changes, reducing EndoMT and vascular damage.</p> Conclusion <p>CAV2 protects against retinal vascular damage and EndoMT in DR, while its deficiency exacerbates pathology via PAI-1 upregulation. The CAV2-PAI-1 axis represents a potential point of intervention for this debilitating condition.</p>

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The CAV2-PAI-1 axis in retinal endothelial dysfunction in diabetic retinopathy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月3日

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  • Jimin Cheng,
  • Jiehui Liu,
  • Fangzheng Ji,
  • Guangying Zheng

摘要

Background

Diabetic retinopathy (DR) is a major cause of vision loss, driven by endothelial dysfunction and endothelial-to-mesenchymal transition (EndoMT). Caveolae and associated proteins like caveolin-2 (CAV2), crucial for vascular homeostasis, may contribute to DR pathogenesis. This study explores the role of CAV2 and its downstream mediator plasminogen activator inhibitor-1 (PAI-1) in retinal vascular damage and EndoMT during DR.

Methods

Transcriptomic profiles of CD31⁺ endothelial cells from fibrovascular membranes of patients with proliferative diabetic retinopathy were analyzed using the GSE94019 dataset to identify differentially expressed caveolae-associated genes. Streptozotocin (STZ)-induced DR was established in C57BL/6J mice, including endothelial-specific CAV2 knockout (EndoCAV2KO) mice generated by breeding CAV2fl/fl with Cdh5-Cre mice. Adeno-associated virus (AAV) vectors were used to overexpress CAV2 or knock down PAI-1. CAV2, CD31, α-smooth muscle actin (α-SMA), vimentin, and PAI-1 expression were assessed via RT-qPCR, Western blot, and immunofluorescence. Retinal structure and vascular permeability were evaluated by hematoxylin–eosin staining and Evans blue assay, respectively. Statistical comparisons were performed using Student's t-test or ANOVA with Tukey's post-hoc test.

Results

Transcriptomic analysis revealed CAV2 downregulation in DR endothelial cells, which was confirmed by reduced CAV2 mRNA and protein levels in retinas of STZ-treated mice. Immunofluorescence demonstrated decreased CAV2 expression specifically in CD31⁺ retinal endothelial cells of diabetic mice. Endothelial CAV2 overexpression attenuated EndoMT, preserved retinal thickness, and decreased vascular permeability. Conversely, EndoCAV2KO mice exhibited exacerbated retinal damage, vascular leakage, and EndoMT, accompanied by elevated PAI-1 levels. PAI-1 knockdown in EndoCAV2KO mice alleviated these pathological changes, reducing EndoMT and vascular damage.

Conclusion

CAV2 protects against retinal vascular damage and EndoMT in DR, while its deficiency exacerbates pathology via PAI-1 upregulation. The CAV2-PAI-1 axis represents a potential point of intervention for this debilitating condition.