The blood flow-klf6a-tagln2 axis drives vessel pruning in zebrafish by regulating endothelial cell rearrangement and actin cytoskeleton dynamics

Author summary Vascular remodeling is critical for vascular physiology and pathology. The primitive vascular plexus formed by angiogenesis, subsequently undergoes extensive vascular remodeling to establish a functionally and hierarchically branched network of blood vessels. Vascular remodeling mainly consists of vessel pruning and fusion. Endothelial cell rearrangement plays an essential role in vessel pruning, which involves endothelial cell migration and polarity. Dysfunction of flow-induced vascular remodeling will cause arteriovenous malformation and impair reperfusion of ischemia stroke. In this study, we show that the large-diameter vessel of the caudal vein is pruned from ventral capillaries of the caudal vein plexus in zebrafish embryos. With this model, we observe a growing difference in blood flow velocity between two branches in vessel pruning. We identify that the klf6a-tagln2 axis regulates CV pruning by promoting endothelial cell rearrangement and junction remodeling. Our results suggest that the caudal vein formation is an ideal model for screening the potential genes involved in vascular remodeling-related disease. Recent studies have focused on capillary pruning in various organs and species. However, the way in which large-diameter vessels are pruned remains unclear. Here we show that pruning of the zebrafish caudal vein (CV) from ventral capillaries of the CV plexus in different transgenic embryos is driven by endothelial cell (EC) rearrangement, which involves EC nucleus migration, junction remodeling, and actin cytoskeleton remodeling. Further observation reveals a growing difference in blood flow velocity between the two vessels in CV pruning in zebrafish embryos. With this model, we identify the critical role of Kruppel-like factor 6a (klf6a) in CV pruning. Disruption of klf6a functioning impairs CV pruning in zebrafish. klf6a is required for EC nucleus migration, junction remodeling, and actin cytoskeleton dynamics in zebrafish embryos. Moreover, actin-related protein transgelin 2 (tagln2) is a direct downstream target of klf6a in CV pruning in zebrafish embryos. Together these results demonstrate that the klf6a-tagln2 axis regulates CV pruning by promoting EC rearrangement.

Automated summary

Vascular remodeling is crucial for maintaining vascular physiology and preventing disease, where endothelial cell rearrangement plays a key role in vessel pruning. The pruning of large-diameter vessels in the zebrafish caudal vein is regulated by the klf6a-tagln2 axis, showcasing its importance in promoting endothelial cell rearrangement.