Key result
High-fat diet plus L-NAME induces an ~8-fold increase in fibroblast AP-1/c-Fos, impairing endothelial autophagy.
Why the study?
The contribution of distinct pulmonary cell subsets to maladaptive lung microenvironmental remodeling and microvascular injury in HFpEF-associated pulmonary hypertension remains incompletely understood.
Does targeting c-Fos-mediated paracrine fibroblast-endothelial signaling restore endothelial homeostasis in a preclinical mouse model of cardiometabolic HFpEF-associated pulmonary hypertension?
Does targeting c-Fos-mediated paracrine fibroblast-endothelial signaling restore endothelial homeostasis in a preclinical mouse model of cardiometabolic HFpEF-associated pulmonary hypertension?
Paracrine fibroblast-to-endothelial signaling mediated by AP-1/c-Fos and S100A4 drives pulmonary microvascular dysfunction and impaired endothelial autophagy in preclinical cardiometabolic HFpEF-associated pulmonary hypertension.
No immediate change to HFpEF-PH care; leaves open cell-specific targeting pending human validation.
Background Pulmonary hypertension (PH) is a common complication of heart failure with preserved ejection fraction (HFpEF) and is associated with worse outcomes than HFpEF alone. Beyond hemodynamic stress, maladaptive remodeling of the lung microenvironment driven by dysfunctional cellular populations may promote pulmonary microvascular injury and PH progression. However, the contribution of distinct pulmonary cell subsets to this remodeling remains incompletely understood. Aim To characterize lung microenvironmental alterations in cardiometabolic HFpEF-associated PH (HFpEF-PH) and to determine whether targeting specific secreted mediators could restore endothelial homeostasis. Methods C57BL/6J mice were fed a control-diet (CD) or a high-fat diet combined with L-NAME for 15 weeks to induce HFpEF-PH. Cardiac and pulmonary function were evaluated by high-resolution echocardiography. Lung tissue underwent single-nucleus RNA sequencing (snRNA-seq). Primary pulmonary endothelial cells (mECs) and fibroblasts (mFBs) were isolated for molecular, metabolic, and autophagic profiling. Paracrine signaling was investigated using co-culture assays and proteomic analysis of fibroblast-media. Autophagic flux was assessed by transmission electron microscopy and protein analysis. The functional role of c-Fos was tested by siRNA-mediated silencing in mFBs. Results HFpEF mice developed PH, with elevated pulmonary pressures, right ventricular hypertrophy, and reduced pulmonary acceleration time. snRNA-seq identified fibroblasts and endothelial cells as the most transcriptionally dysregulated populations, characterized by expansion of activated myofibroblast subsets and upregulation of AP-1 complex genes, with HFpEF-PH fibroblasts exhibiting an eightfold increase in AP-1/cFos expression compared to controls, alongside a profibrotic phenotype and metabolic reprogramming. mECs showed inflammatory activation and impaired autophagic flux,confirmed ultrastructurally by the accumulation of immature autophagosomes. Interactome analysis identified fibroblasts as the main source of intercellular signalling in HFpEF-PH lungs. Conditioned media from HFpEF-PH fibroblasts reproduced autophagic defects in healthy mECs, suggesting a paracrine, AP-1–mediated mechanism of endothelial injury. Proteomic analysis of the HFpEF-PH fibroblast secretome identified key inflammatory and profibrotic mediators. In particular, S100A4, a calcium-binding protein, was detected and implicated in endothelial dysfunction and extracellular matrix remodeling. Exposure of CD-mECs to HFpEF-mFB-conditioned media reproduced endothelial dysfunction, which was rescued by c-Fos silencing in myofibroblasts, normalizing S100A4 levels and restoring autophagic flux. Conclusion Fibroblast–endothelial communication emerges as a key driver of microvascular dysfunction in HFpEF–PH, offering new therapeutic opportunities to counteract pulmonary vascular remodeling.fos1fos2
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Telesca et al. (2026) studied Cardiometabolic heart failure with preserved ejection fraction-associated pulmonary hypertension (HFpEF-PH). High-fat diet combined with L-NAME and siRNA-mediated c-Fos silencing in pulmonary fibroblasts vs. Control diet was evaluated on Lung microenvironmental alterations, fibroblast AP-1/c-Fos expression, and endothelial autophagic flux (8-fold increase in AP-1/c-Fos expression). High-fat diet plus L-NAME induced an 8-fold increase in fibroblast AP-1/c-Fos expression and impaired endothelial autophagy, which was rescued by c-Fos silencing.
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