Potential role of embryonic haemodynamic experience in the emergence of the arterial–venous dichotomy

While the segregation of the nascent vascular plexus into arterial and venous compartments with distinct molecular signatures has long been accepted as a fundamental organising principle in vertebrate development, the factors that precipitate this bifurcation remain poorly understood. Here we outline a developmental account in which early haemodynamic experience is a primary driver. Specifically, we propose that the nearly simultaneous maturation of pulsatile shear forces and oxygen‐tension gradients acts in concert to sculpt the transcriptional programmes that ultimately define arterial versus venous identity. Single-cell trajectory analyses of agent-based endothelial simulations trained under developmentally informed ‘biomimetic’ protocols support this proposal across both spatial and temporal scales. Model vessels exposed to appropriately timed shear-stress waveforms and graded hypoxia spontaneously resolved into two stable gene-expression attractors mirroring canonical arterial (Notch/EFNB2-high) and venous (COUP-TFII/EphB4-high) states. Moreover, biomimetic training imposed a pronounced bias toward hierarchical, tree-like branching reminiscent of human vascular topology, a feature preferentially initiated by emergent arterial-like tip cells. These findings illuminate a plausible mechanism for a central aspect of vascular patterning and offer practical guidance for refining differentiation and bioreactor regimens in regenerative fabrication of blood vessels.