Lambiase, G.; Moshe, N.; Raanan, C.; Das, R. N.; Yaniv, K.

The Inferior Vena Cava (IVC), the largest venous conduit in mammals, forms through complex remodeling of the embryonic cardinal veins (CVs), a process prone to congenital anomalies, with significant clinical implications. However, the mechanisms underlying IVC formation remain unclear. Here, we identify a conserved IVC in zebrafish that emerges during metamorphosis through remodeling of the embryonic CVs, mirroring the mammalian process. Using in vivo imaging and clonal lineage tracing, we identify the cellular origins and molecular mechanisms controlling IVC formation and demonstrate that the transition from CV to IVC represents a shift from a multifunctional embryonic vein to a specialized adult conduit adapted for high-volume blood return. Overall, our findings illuminate conserved mechanisms of venous remodeling and establish a foundation for investigating congenital venous anomalies.