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Background <p>Gestational diabetes mellitus (GDM), a prevalent prenatal metabolic disorder characterized by hyperglycemia occurring in approximately 9.2% of pregnancies globally, imposes significant cardiovascular risks on offspring, including developmental cardiac hypertrophy and long-term functional impairment. Despite its clinical importance, the molecular mechanisms governing GDM-induced cardiac malformations remain elusive.</p> Aims <p>This study aimed to delineate the regulatory role of the Wnt/β-catenin/Tcf7l2 signaling pathway in mediating pathological cardiac remodeling in GDM-exposed offspring through experimental manipulation using a clinically relevant murine model.</p> Methods <p>We established a clinically relevant GDM mouse model exhibiting key metabolic features including hyperinsulinemia and impaired glucose tolerance, which faithfully recapitulates human GDM pathology. Cardiomyocyte-specific β-catenin knockout and cardiomyocyte-specific overexpression of constitutively active β-catenin were employed for genetic manipulation. Pharmacological intervention was performed using saxagliptin, a clinically approved DPP-4 inhibitor. Cardiac phenotypes were evaluated by histopathological analysis, echocardiography, and molecular assessments of Wnt/β-catenin pathway activity and hypertrophic markers.</p> Results <p>Histopathological and echocardiographic analyses revealed pronounced cardiac hypertrophy in GDM-exposed offspring, concomitant with activation of the Wnt/β-catenin/Tcf7l2 pathway in myocardial tissues. Functional studies demonstrated that cardiomyocyte-specific β-catenin ablation attenuated GDM-induced hypertrophic remodeling, whereas constitutive β-catenin overexpression exacerbated cardiac dysfunction. Importantly, pharmacological intervention with saxagliptin significantly ameliorated cardiac hypertrophy in GDM-offspring. This therapeutic effect was paralleled by marked suppression of Wnt/β-catenin signaling activity and reduced expression of ANP.</p> Conclusion <p>Collectively, these findings provide compelling evidence that dysregulation of the Wnt/β-catenin/Tcf7l2 pathway constitutes a critical mediator in GDM-induced cardiac hypertrophy, and highlight saxagliptin as a potential therapeutic strategy to mitigate adverse cardiac outcomes in GDM offspring.</p> <p></p>

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Reversal of canonical Wnt/β-catenin signaling pathway attenuates gestational diabetes mellitus-induced offspring cardiac hypertrophy: mechanistic insights into pathological remodeling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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  • Xun Yuan,
  • Yuejiang Jiao,
  • Zexin Huang,
  • Ruchao Jiang,
  • Yiling Chen,
  • Ducai Liu,
  • Zexin Zhao,
  • Qiulian Zhu,
  • Yuan Qin,
  • Guiping Zhang,
  • Zhimei Feng,
  • Caixian Yang,
  • Ning Hou

摘要

Background

Gestational diabetes mellitus (GDM), a prevalent prenatal metabolic disorder characterized by hyperglycemia occurring in approximately 9.2% of pregnancies globally, imposes significant cardiovascular risks on offspring, including developmental cardiac hypertrophy and long-term functional impairment. Despite its clinical importance, the molecular mechanisms governing GDM-induced cardiac malformations remain elusive.

Aims

This study aimed to delineate the regulatory role of the Wnt/β-catenin/Tcf7l2 signaling pathway in mediating pathological cardiac remodeling in GDM-exposed offspring through experimental manipulation using a clinically relevant murine model.

Methods

We established a clinically relevant GDM mouse model exhibiting key metabolic features including hyperinsulinemia and impaired glucose tolerance, which faithfully recapitulates human GDM pathology. Cardiomyocyte-specific β-catenin knockout and cardiomyocyte-specific overexpression of constitutively active β-catenin were employed for genetic manipulation. Pharmacological intervention was performed using saxagliptin, a clinically approved DPP-4 inhibitor. Cardiac phenotypes were evaluated by histopathological analysis, echocardiography, and molecular assessments of Wnt/β-catenin pathway activity and hypertrophic markers.

Results

Histopathological and echocardiographic analyses revealed pronounced cardiac hypertrophy in GDM-exposed offspring, concomitant with activation of the Wnt/β-catenin/Tcf7l2 pathway in myocardial tissues. Functional studies demonstrated that cardiomyocyte-specific β-catenin ablation attenuated GDM-induced hypertrophic remodeling, whereas constitutive β-catenin overexpression exacerbated cardiac dysfunction. Importantly, pharmacological intervention with saxagliptin significantly ameliorated cardiac hypertrophy in GDM-offspring. This therapeutic effect was paralleled by marked suppression of Wnt/β-catenin signaling activity and reduced expression of ANP.

Conclusion

Collectively, these findings provide compelling evidence that dysregulation of the Wnt/β-catenin/Tcf7l2 pathway constitutes a critical mediator in GDM-induced cardiac hypertrophy, and highlight saxagliptin as a potential therapeutic strategy to mitigate adverse cardiac outcomes in GDM offspring.