Scube2 Modulates Coronary Vessel Formation during Cardiac Growth and Regeneration in Zebrafish

Lai, S.-L. B.; Lee, A. N.; Wei, K.-H.; Chowdhury, K.; Rouf, M. A.; Chu, A.-J.; Hung, Y.-J.; Tsao, K.-C.; Chen, Y.-T.; Lin, Y.-C.; Chang, Y.-M.; Marin-Juez, R.; Yang, R.-B.

doi:10.64898/2025.12.17.695032

bioRxiv · 10.64898/2025.12.17.695032

Scube2 Modulates Coronary Vessel Formation during Cardiac Growth and Regeneration in Zebrafish

Lai, S.-L. B.·Lee, A. N.·Wei, K.-H.·Chowdhury, K.·Rouf, M. A.·Chu, A.-J.·Hung, Y.-J.·Tsao, K.-C.·Chen, Y.-T.·Lin, Y.-C.·Chang, Y.-M.·Marin-Juez, R.·Yang, R.-B.

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Abstract

Coronary vessel formation is essential for cardiac growth and regeneration, yet the mechanisms regulating these processes remain incompletely defined. In this study, we identified and characterized Scube2 as a novel regulator in coronary vessel formation and heart regeneration. Scube2 is expressed in the epicardium covering the coronary vasculature under homeostatic conditions in adult hearts and is strongly upregulated after cardiac injury. Zebrafish scube2 mutant exhibits reduced coronary vessel coverage during cardiac growth and pronounced myocardial defects, including abnormal vessel morphology, disorganized contractile fibers, and mitochondrial damage. Following injury, scube2 mutant hearts show impaired revascularization and persistent fibrosis, indicating defective regeneration. Mechanistically, transcriptomic profiling of scube2 mutant hearts reveals attenuated expression of angiogenic-related genes, including those mediated by vascular endothelial and platelet-derived growth factors, consistent with reduced proliferation of endothelial cells and cardiomyocytes during repair. In a gain-of-function setting, SCUBE2 enhances platelet-derived growth factor signaling by promoting receptor activation in HEK293 cells. These findings support a novel role for Scube2 in cardiac growth and regeneration by modulating coronary vessel formation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/695032v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@7c5b5org.highwire.dtl.DTLVardef@451c40org.highwire.dtl.DTLVardef@141c88forg.highwire.dtl.DTLVardef@1d63765_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Lai, S.-L. B., Lee, A. N., Wei, K.-H., Chowdhury, K., Rouf, M. A., Chu, A.-J., Hung, Y.-J., Tsao, K.-C., Chen, Y.-T., Lin, Y.-C., Chang, Y.-M., Marin-Juez, R., Yang, R.-B.. 2025-12-19. Scube2 Modulates Coronary Vessel Formation during Cardiac Growth and Regeneration in Zebrafish. https://doi.org/10.64898/2025.12.17.695032

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