Circulation research · 2026
FGFR1/KLB-MFG-E8 Maintains Microvascular Integrity and Adaptive Cardiac Remodeling.
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Gare Sanskruti R, Alatawi Nasser H, Chen Xinyi, Zhang Jiayan, Ross Claire, Fonseka Oveena, Han Yihua, Kaur Namrita, Ruiz-Velasco Andrea, Zhao Xiangjun, Liu Yingjuan, Abouleisa Riham R E, Hille Susanne S, Wang Tao, Abraham Sabu, Keavney Bernard D, Rutter Martin K, Cartwright Elizabeth J, Howell Gareth, Mohamed Tamer M A, Müller Oliver J, Liu Wei
Аннотация
BACKGROUND: Endothelial defects in the heart are a contributor to cardiac pathological remodeling and dysfunction, which can be influenced by cardiomyocytes. Here, we explore cardioprotective crosstalk between cardiomyocytes and endothelial cells under diabetic conditions.
METHODS: Type 2 diabetes was induced in male and female mice using a high-fat, high-sucrose diet in conjunction with low-dose streptozotocin. Cardiomyocyte-specific deletion of FGFR1 (fibroblast growth factor receptor 1) or KLB (beta-Klotho) was achieved by crossing floxed mice with αMHC (alpha-myosin heavy chain)-Cre transgenic mice, while the treatment potential was assessed by recombinant adeno-associated virus 9 delivery systems or administration of recombinant protein. Various in vitro models were used to investigate the mechanisms under a diabetes-like condition. The molecular mechanisms were explored through transcriptomics, proteomics, cytokine arrays, angiogenesis assays, histology, and luciferase reporter assays.
RESULTS: Human diabetic hearts exhibited impaired angiogenic pathways with a marked reduction in myocardial capillary density. Multiomics profiling also revealed alterations in the FGFR1 (fibroblast growth factor receptor 1) pathway in mouse diabetic hearts. Both cardiomyocyte-specific FGFR1- and KLB- knockout mice exhibited reduced capillary abundance and developed decompensated cardiac remodeling. Mechanistic studies identified CEBPβ (CCAAT/enhancer binding protein beta) as a downstream transcription factor of the FGFR1/KLB pathway regulating MFG-E8 (milk fat globule-EGF factor 8) expression in cardiomyocytes. Cardiomyocyte-secreted MFG-E8 enhanced endothelial viability and branching. Importantly, the detrimental effects on the heart were rescued by corestoration of cardiac FGFR1 and KLB, whereas neither alone was sufficient, underscoring their synergistic action against diabetic stress. Finally, genetic or pharmacological enhancement of MFG-E8 reversed myocardial capillary rarefaction and led to an improvement in cardiac function, albeit with more pronounced therapeutic effects in males.
CONCLUSIONS: Our findings demonstrate FGFR1/KLB-mediated cardioprotective mechanisms through cardiomyocyte-endothelial cell crosstalk and provide evidence that preserving adaptive remodeling represents a promising strategy to alleviate heart failure in both sexes.
METHODS: Type 2 diabetes was induced in male and female mice using a high-fat, high-sucrose diet in conjunction with low-dose streptozotocin. Cardiomyocyte-specific deletion of FGFR1 (fibroblast growth factor receptor 1) or KLB (beta-Klotho) was achieved by crossing floxed mice with αMHC (alpha-myosin heavy chain)-Cre transgenic mice, while the treatment potential was assessed by recombinant adeno-associated virus 9 delivery systems or administration of recombinant protein. Various in vitro models were used to investigate the mechanisms under a diabetes-like condition. The molecular mechanisms were explored through transcriptomics, proteomics, cytokine arrays, angiogenesis assays, histology, and luciferase reporter assays.
RESULTS: Human diabetic hearts exhibited impaired angiogenic pathways with a marked reduction in myocardial capillary density. Multiomics profiling also revealed alterations in the FGFR1 (fibroblast growth factor receptor 1) pathway in mouse diabetic hearts. Both cardiomyocyte-specific FGFR1- and KLB- knockout mice exhibited reduced capillary abundance and developed decompensated cardiac remodeling. Mechanistic studies identified CEBPβ (CCAAT/enhancer binding protein beta) as a downstream transcription factor of the FGFR1/KLB pathway regulating MFG-E8 (milk fat globule-EGF factor 8) expression in cardiomyocytes. Cardiomyocyte-secreted MFG-E8 enhanced endothelial viability and branching. Importantly, the detrimental effects on the heart were rescued by corestoration of cardiac FGFR1 and KLB, whereas neither alone was sufficient, underscoring their synergistic action against diabetic stress. Finally, genetic or pharmacological enhancement of MFG-E8 reversed myocardial capillary rarefaction and led to an improvement in cardiac function, albeit with more pronounced therapeutic effects in males.
CONCLUSIONS: Our findings demonstrate FGFR1/KLB-mediated cardioprotective mechanisms through cardiomyocyte-endothelial cell crosstalk and provide evidence that preserving adaptive remodeling represents a promising strategy to alleviate heart failure in both sexes.