Slc35a1-mediated endothelial sialylation controls the fate and integrity of the intestinal microvascular network in adult mice.

Vascular endothelial cells express abundant sialylated glycans, but their function remains unclear. To determine the role of endothelial overall sialylation, which is controlled by Slc35a1, in adult mice. We generated mice with inducible deletion of Slc35a1 in endothelial cells (iEHC Slc35a1-/-) using tamoxifen-inducible Cdh5CreERT2. Induced deletion of Slc35a1 in adulthood caused progressive weight loss, anemia, and spontaneous intestinal bleeding. Adult intestinal villus capillaries exhibited disorganized networks, loss of vascular integrity, and bleeding. Multiplexed Error-Robust Fluorescence in Situ Hybridization spatial transcriptomic analysis revealed downregulation of endothelial genes essential for angiogenesis and endothelial specialization, including Vegfr2, Cdh5, and Plvap. Immunostaining confirmed loss of VEGFR2, disorganized VE-cadherin junctions, and impaired PLVAP-dependent capillary fenestration. Endothelial Slc35a1 deletion also reduced endothelial von Willebrand factor expression and plasma multimerization, indicating impaired hemostatic function. Our results reveal new roles for Slc35a1-dependent endothelial sialylation in maintaining the fate and integrity of the intestinal microvascular network in adult mice.