Non-canonical VEGFA N-terminal peptide functions as a nuclear regulator driving age-dependent cardiac remodelling

Background Vascular endothelial growth factor A (VEGFA) is a dosage-sensitive regulator of cardiovascular development, and even subtle perturbations in its expression profoundly affect cardiac structure and survival1. Beyond canonical AUG-initiated translation that generates secreted angiogenic isoforms, VEGFA also undergoes non-canonical CUG-initiated translation, producing an N-terminal peptide (N-VEGFA)2. While VEGFA has been extensively studied as a paracrine angiogenic factor, the in vivo relevance and potential cell-autonomous role of its N-terminal product in the adult heart remain undefined. Purpose To determine whether N-VEGFA exerts a nuclear function in cardiomyocytes and contributes to age-dependent cardiac remodelling. Methods A mouse model selectively lacking N-VEGFA was analysed longitudinally using echocardiography and electrocardiography. Subcellular localisation was assessed in vivo and in cardiomyocyte-specific AAV overexpression models. CUT&Tag profiling was performed to define genome-wide chromatin binding landscapes under homeostatic and post-infarction conditions. Results Although cardiac development and coronary architecture were preserved3, N-VEGFA-deficient mice developed progressive systolic dysfunction with ageing, accompanied by QRS and T-wave prolongation, indicating combined contractile and electrophysiological impairment. In vivo analyses demonstrated nuclear localisation of N-VEGFA in cardiomyocytes, whereas truncation markedly reduced nuclear presence. Genome-wide chromatin profiling identified discrete N-VEGFA binding sites enriched near genes governing cardiomyocyte differentiation, structural remodelling and stress adaptation. Following myocardial infarction, stress-associated redistribution of binding sites was observed. Motif analysis revealed significant enrichment of MEF2 and TEAD transcription factor binding motifs within N-VEGFA-associated enhancer regions, supporting cooperative regulation of cardiac stress transcriptional programmes. Conclusion Beyond its established angiogenic function, the VEGFA N-terminal peptide operates as a nuclear regulator in cardiomyocytes. Loss of this non-canonical isoform promotes age-dependent contractile decline and electrical conduction abnormalities, uncovering a previously unrecognised mechanism linking translational diversity to cardiac remodelling.