FGFR1/KLB-MFG-E8 Maintains Microvascular Integrity and Adaptive Cardiac Remodeling

Abstract

Background: Endothelial defects in the heart are a contributor to cardiac pathological remodeling and dysfunction, which can be influenced by cardiomyocytes (CMs). Here, we explore cardioprotective crosstalk between CMs and endothelial cells (ECs) under diabetic conditions. Methods: Type 2 diabetes mellitus (T2DM) was induced in male and female mice using a high-fat, high-sucrose diet (HFHSD) in conjunction with low-dose streptozotocin (STZ). CM-specific deletion of FGFR1 or KLB 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 (AAV9) delivery systems or administration of recombinant protein. Various in vitro models were utilized 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 CM-specific FGFR1- and KLB (beta-Klotho)-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 CMs. CM-secreted MFG-E8 enhanced endothelial viability and branching. Importantly, the detrimental effects on the heart were rescued by co-restoration of cardiac FGFR1 and KLB, whereas neither alone overexpression 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 CM-EC crosstalk and provide evidence that preserving adaptive remodeling represents a promising strategy to alleviate heart failure in both sexes.