Jo et al. identify the plasma membrane Ca2+−pump ATP2B1/PMCA1 as a regulator of endothelial Norrin/Frizzled4 and Wnt signaling in the CNS vasculature. Loss of ATP2B1 elevates intracellular Ca2+ and activates NFAT, suppressing β-catenin signaling and linking Ca2+ homeostasis to angiogenesis and blood-brain barrier integrity.