BioProject

Hemodynamic cues are thought to control blood vessel hierarchy through a shear stress set point, where flow increases lead to blood vessel diameter expansion, while decreases in blood flow cause blood vessel narrowing. More...

Hemodynamic cues are thought to control blood vessel hierarchy through a shear stress set point, where flow increases lead to blood vessel diameter expansion, while decreases in blood flow cause blood vessel narrowing. Aberrations in blood vessel diameter control can cause congenital arteriovenous malformations (AVMs). We show in zebrafish embryos that while arteries behave according to the shear stress set point model, veins do not. This behavior is dependent on distinct arterial and venous endothelial cell (EC) shapes and sizes. Through blood flow manipulations, we show that arterial ECs enlarge more strongly when experiencing higher flow, as compared to vein cells. Through the generation of chimeric embryos, we discover that this refractory behavior of vein cells depends on the Bone Morphogenetic Protein (BMP) pathway components Endoglin and Alk1. In contrast to eng or alk1 mutant arterial ECs, mutant vein cells enlarge when in normal hemodynamic environments. We further show that an increase in vein diameters initiates AVMs in endoglin mutants, secondarily transmitting higher flow to arteries. These enlarge in response to higher flow, fueling the AVM. Finally, single cell sequencing results indicate that increases in vein EC sizes in endoglin mutants are likely caused by increases in ribosome biogenesis and downregulation of the translational inhibitor dap1b. This study thus reveals a mechanism through which BMP signaling limits vein EC size increases in response to flow and provides a framework for our understanding of how a small number of mutant vein cells via flow-mediated secondary effects on wildtype arterial ECs can precipitate larger AVMs in disease conditions, such as hereditary hemorrhagic telangiectasia (HHT). Overall design: Endothelial cells of 3 dpf Tg(kdrl:EGFP) zebrafish embryos with two genotypes, WT and Endoglin mutant (Eng-/-), were isolated by FACS and analyzed by scRNAseq separately. Less...