A conserved biphasic venous remodeling program governs inferior vena cava formation in zebrafish

The Inferior Vena Cava (IVC), the largest vein in humans, develops through replacement of the embryonic cardinal veins (CVs), a complex process prone to congenital anomalies, with major clinical implications. Yet, the mechanisms underlying IVC formation remain unclear. Here, we identify the zebrafish IVC, which emerges during metamorphosis and replaces the embryonic CVs, following a biphasic sequence similar to that described in mammals. Using longitudinal imaging and clonal lineage tracing, we demonstrate that the IVC originates exclusively from preexisting venous endothelial cells. Unexpectedly, genetic and pharmacological perturbations reveal that IVC formation proceeds independently of Vegfc/Vegfr3 signaling and instead involves Vegfa-dependent venous sprouting. Last, we demonstrate that the transition from CV to IVC marks a shift from a multifunctional embryonic vein to a specialized adult conduit adapted for high-volume blood transport. Overall, we identify a venous morphogenesis program akin to the mammalian IVC formation, providing a foundation for investigating venous anomalies.