The sympathoadrenal contribution to inferior vena cava formation
Vascular development is fundamental during embryogenesis. Although the molecular and cellular mechanisms of vascular formation have been extensively studied, the developmental basis common to anatomical variations in major veins remains poorly understood1-4. In particular, the renal segment of the inferior vena cava (IVC) exhibits marked anatomical variability, and these structural differences often affect the safety of retroperitoneal surgeries5,6. Here we show that the renal segment of the IVC in mouse embryos does not arise from the subcardinal vein (SubCV), as classically proposed7, but instead forms from a vascular plexus in the para-aortic ridge (PAR) closely associated with developing sympathetic and adrenal tissues. Three-dimensional imaging with molecular markers revealed the vascular plexus in PAR arises independently of the SubCV and develops in Zuckerkandl organ and adrenal gland primordia. Moreover, genetic models demonstrated that the development of the sympathetic and adrenal tissues contributes to the organization and remodeling of this vascular network. This sympathoadrenal contribution contrasts with the classical mesonephros-centric model and explains the consistent IVC structures observed even in the absence of renal development. Our findings suggest a mammal-specific mode of IVC formation driven by the emergence of dominant sympathetic paraganglia and reduced reliance on mesonephric filtration. This revised developmental framework provides insight into the evolutionary divergence of venous anatomy and may help interpret clinically significant vascular variations during abdominal surgery.