Scube2 promotes PDGF-dependent coronary vessel formation and cardiac regeneration in zebrafish

Coronary vessel formation is vital for healthy cardiac growth and regeneration, yet the precise extracellular mechanisms governing this complex vascular remodeling remain poorly understood. Current approaches to enhance cardiac repair often fall short due to insufficient revascularization. While Scube2 (signal peptide-CUB-EGF domain-containing protein 2) has been implicated in developmental vascular signaling, its specific role in coronary vessel development and post-injury cardiac regeneration had not been established.

Researchers investigated Scube2 function in zebrafish using genetic loss-of-function mutants and inducible global/epicardial-specific dominant-negative models. Cardiac regeneration was induced via cryoinjury. They employed confocal and ultrastructural imaging, bulk RNA sequencing, and biochemical analyses to examine signaling mechanisms. This allowed for detailed assessment of coronary vessel formation, myocardial structure, and regenerative capacity under various Scube2 manipulations.

Scube2 was found in the epicardium under normal conditions and rapidly induced in epicardial-derived cells post-injury. Loss of Scube2 severely impaired developmental coronary vessel formation and caused myocardial ultrastructural abnormalities. Following injury, Scube2 deficiency led to defective revascularization, reduced mural cell association, decreased endothelial and cardiomyocyte proliferation, persistent fibrosis, and impaired cardiac regeneration.

Temporal and epicardial-specific inhibition of Scube2 recapitulated these regenerative defects, highlighting its critical role. Transcriptomic analyses revealed dysregulation of VEGF and PDGF signaling pathways, alongside reduced endothelial proliferation and prolonged inflammatory responses. Mechanistically, SCUBE2 interacted directly with PDGF-B and PDGFRβ, enhancing PDGFRβ activation, which is crucial for endothelial-mural cell communication during vascular remodeling.