Computational Simulations of Trigger-and-Inhibit Control Rules in Intussusceptive Pillar Morphogenesis

Abstract Intussusceptive angiogenesis (IA) enables rapid microvascular expansion through the formation of intraluminal tissue pillars that split pre-existing vessels without endothelial proliferation. Despite its biological and clinical relevance, the initiating mechanisms governing pillar formation remain poorly defined. Here, we used computational fluid dynamics to test the hypothesis that pillar morphogenesis follows trigger–and–inhibit microhemodynamic control rules. In this framework, steep wall shear stress gradients (WSSG) trigger pillar initiation while elevated absolute wall shear stress (WSS) suppresses remodeling. Using finite element–based computational flow modeling of the chick chorioallantoic membrane, we analyzed local flow fields at five canonical pillar sites: convergent and divergent branch points, capillary entry and exit boundaries, and post-capillary microthrombi. Across all locations, predicted pillar positions coincided with interfaces where elevated WSSG abutted low-WSS domains within microns. These findings support a threshold-based, flow-responsive model of IA in which the spatial distribution of shear—not shear magnitude alone—governs pillar formation and microvascular network remodeling.