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Background <p>Diabetic cardiomyopathy (DCM) is characterized by microvascular dysfunction. While vascular endothelial cells (ECs) have been widely studied, the role of cardiac lymphatic ECs (LECs) in DCM remains unknown.</p> Methods <p>A mouse model of DCM was induced by a high-fat diet (HFD) with streptozotocin (STZ) injection. We performed single-cell RNA sequencing (scRNA-seq) on cardiac tissues from mice with DCM and control mice. We then applied clustering, RNA velocity, pseudotime analysis, and CellChat cell-cell communication analysis to define lymphatic endothelial cell (LEC) heterogeneity and underlying regulatory networks.</p> Results <p>Our analysis revealed profound pathological remodeling of the cardiac lymphatic architecture in diabetic hearts, marked by decreased LEC numbers and impaired function. Cell-cell communication analysis demonstrated impaired VEGF-C/VEGFR3 signaling between venous ECs (VECs) and LECs in diabetic hearts. We identified the upregulation of pyruvate dehydrogenase kinase 4 (PDK4) expression in diabetic LECs as a key driver of metabolic reprogramming, leading to impaired cell migration.</p> Conclusions <p>This study mapped the profile of LECs in diabetic hearts and revealed a dual pathogenic mechanism involving metabolic disorders driven by PDK4 and disruption of venous-lymphatic communication. These findings may provide new strategies for the treatment of DCM.</p>

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Single-cell transcriptomic profiling reveals PDK4 upregulation and impaired VEGF-C/VEGFR3 signaling in cardiac lymphatic endothelial cells in diabetic cardiomyopathy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月16日

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  • Yufeng Yan,
  • Xunuo Wang,
  • Congfei Zhu,
  • Zihao Jiang,
  • Jing Wang,
  • Junjie He,
  • Lei Xu,
  • Xiaobin Zhou,
  • Qing Ge,
  • Zuoying Hu,
  • Guangfeng Zuo

摘要

Background

Diabetic cardiomyopathy (DCM) is characterized by microvascular dysfunction. While vascular endothelial cells (ECs) have been widely studied, the role of cardiac lymphatic ECs (LECs) in DCM remains unknown.

Methods

A mouse model of DCM was induced by a high-fat diet (HFD) with streptozotocin (STZ) injection. We performed single-cell RNA sequencing (scRNA-seq) on cardiac tissues from mice with DCM and control mice. We then applied clustering, RNA velocity, pseudotime analysis, and CellChat cell-cell communication analysis to define lymphatic endothelial cell (LEC) heterogeneity and underlying regulatory networks.

Results

Our analysis revealed profound pathological remodeling of the cardiac lymphatic architecture in diabetic hearts, marked by decreased LEC numbers and impaired function. Cell-cell communication analysis demonstrated impaired VEGF-C/VEGFR3 signaling between venous ECs (VECs) and LECs in diabetic hearts. We identified the upregulation of pyruvate dehydrogenase kinase 4 (PDK4) expression in diabetic LECs as a key driver of metabolic reprogramming, leading to impaired cell migration.

Conclusions

This study mapped the profile of LECs in diabetic hearts and revealed a dual pathogenic mechanism involving metabolic disorders driven by PDK4 and disruption of venous-lymphatic communication. These findings may provide new strategies for the treatment of DCM.