Vegfa signaling ameliorates cardiac fibrosis and restores endothelial regeneration in a point-mutated zebrafish model of pseudoxanthoma elasticum.

The ABCC6 gene is associated with pseudoxanthoma elasticum (PXE), a genetic disorder characterized by ectopic calcification in soft tissues, notably affecting the cardiovascular system. However, the underlying cardiovascular pathological mechanisms remain elusive and effective treatments are currently unavailable. Here, we employed a point-mutated zebrafish model harboring the abcc6aR1463C/R1463C mutation (orthologous to the human ABCC6R1459C variant) to investigate the cardiac homeostasis and regeneration. We find that abcc6a deficiency leads to enhanced TGF-β/Smad3 signaling and vegfaa overexpression ameliorates abcc6a deficiency-induced cardiac fibrosis and mitochondrial ultrastructural defects. Moreover, abcc6aR1463C/R1463C mutants exhibit coronary vasculature malformations, impaired endothelial proliferation and compromised revascularization post-cardiac injury. Transcriptomic profiling reveals upregulated genes associated with the extracellular matrix (ECM) and downregulated genes involved in signal transduction and circulatory system (vegfaa, vegfc, notch1a, notch1b, dll4). vegfaa overexpression in abcc6aR1463C/R1463C mutants attenuates cardiac pathologies by restoring endothelial proliferation, resolving fibrosis, and enhancing injury repair. Mechanistically, vegfaa acts via Notch signaling to ameliorate endocardial deficits and functional impairments. Our findings establish abcc6a as a critical regulator of cardiac resilience, coordinating anti-fibrotic and pro-regenerative responses, and propose Vegfa and Notch pathways as therapeutic synergy for PXE-related cardiovascular pathophysiology.