Blood flow coordinates collective endothelial cell migration during vascular plexus formation and promotes angiogenic sprout regression via vegfr3/flt4

Nascent vascular networks adapt to the increasing metabolic demands of growing tissues by expanding via angiogenesis. As vascular networks expand, blood vessels remodel, progressively refining vascular connectivity to generate a more haemodynamically efficient network. This is driven by interplay between endothelial cell (EC) signalling and blood flow. While much is known about angiogenesis, less is understood of how blood flow remodels vessels. Here we employ the zebrafish sub-intestinal venous plexus (SIVP) to characterise blood flow-dependent remodelling. Using live imaging to track ECs we show that blood flow controls SIVP remodelling by coordinating collective EC migration within the developing plexus. Blood flow opposes continuous ventral EC migration within the SIVP and is required for angiogenic sprout regression to support plexus growth. Sprout regression occurs by coordinated migration of ECs from non-perfused leading sprouts, which migrate against blood flow and incorporate into the sub-intestinal vein. Sprout regression remains compatible with low blood flow but requires vegfr3/flt4 function under these conditions. Collectively, these studies reveal how blood flow sculpts a developing vascular plexus by coordinating EC migration and balancing vascular remodelling via vegfr3/flt4.