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

Q: What is the clinical evidence from this study?

Population: Diabetic cardiomyopathy (n=4). Intervention: High-fat diet and streptozotocin vs. Standard laboratory diet and vehicle injection. Primary outcome: Single-cell transcriptomic profile of cardiac lymphatic endothelial cells.

Q: What does this research mean for the field?

Diabetic cardiomyopathy induces pathological remodeling and dysfunction of cardiac lymphatic endothelial cells, driven by PDK4-mediated metabolic reprogramming and impaired VEGF-C/VEGFR3 signaling. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

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

doi:10.1186/s10020-026-01571-9

July 15, 2026Molecular MedicineOpen Access

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

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Key result

PDK4 upregulation drives cardiac lymphatic endothelial remodeling in diabetic cardiomyopathy via impaired VEGF-C/VEGFR3 signaling.

n=4

Why the study?

Diabetic cardiomyopathy is characterized by microvascular dysfunction, but the role of cardiac lymphatic endothelial cells remains unknown.

Key Points

Investigate cardiac lymphatic endothelial cell heterogeneity, transcriptomic remodeling, and intercellular regulatory networks in diabetic cardiomyopathy.
Induced diabetic cardiomyopathy in mice using a high-fat diet combined with streptozotocin injection, evaluating cardiac and metabolic function at 24 weeks post-modeling.
Performed single-cell RNA sequencing on cardiac tissues, profiling 61,748 high-quality cells (29,900 from control and 31,848 from diabetic cardiomyopathy hearts) categorized into 13 major cell types across 34 clusters.
Analyzed 12,599 cardiac endothelial cells using clustering, RNA velocity, Monocle2 pseudotime trajectories, and CellChat cell-cell communication analysis.
Diabetic hearts exhibited structural remodeling and impaired lymphatic function, accompanied by decreased venous endothelial cell numbers and increased capillary endothelial cell proportions.
Cell-cell communication analysis demonstrated impaired VEGF-C/VEGFR3 signaling between venous endothelial cells and lymphatic endothelial cells in diabetic hearts.
Pyruvate dehydrogenase kinase 4 (PDK4) was upregulated in diabetic lymphatic endothelial cells, driving metabolic reprogramming and activating pathways that negatively regulate cell migration.

Structured PICO

P

Population

4 male C57BL/6J mice used to model diabetic cardiomyopathy via high-fat diet and streptozotocin injection for single-cell RNA sequencing.

I

Intervention

High-fat diet and streptozotocin to induce diabetic cardiomyopathy (in vivo); high glucose and palmitate with or without PDK4 inhibition/knockdown/overexpression (in vitro).

C

Comparator

Age-matched control mice on standard diet with vehicle injections (in vivo); low glucose (in vitro).

O

Outcome

Lymphatic endothelial cell heterogeneity, pathological remodeling, and underlying regulatory networks assessed by single-cell RNA sequencing.surrogate

This preclinical study identifies PDK4 upregulation and disrupted venous-lymphatic VEGF-C/VEGFR3 communication as key mechanisms of cardiac lymphatic endothelial cell dysfunction in diabetic cardiomyopathy.

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Implication

Suggests lymphatic endothelial remodeling as a novel target in diabetic cardiomyopathy; leaves open translation of PDK4/VEGF-C findings to human disease.

Abstract

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.

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Cite This Study

Yan et al. (2026) studied Diabetic cardiomyopathy (n=4). High-fat diet and streptozotocin vs. Standard laboratory diet and vehicle injection was evaluated on Single-cell transcriptomic profile of cardiac lymphatic endothelial cells. In a mouse model of diabetic cardiomyopathy, single-cell RNA sequencing revealed pathological remodeling of cardiac lymphatic endothelial cells driven by PDK4 upregulation and impaired VEGF-C/VEGFR3 signaling.

synapsesocial.com/papers/6a5b172618557b26c2039705 https://doi.org/10.1186/s10020-026-01571-9

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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

Key Points

Structured PICO

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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

Key Points

Structured PICO

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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