CD98hc controls CNS angiogenesis and blood-brain barrier integrity through localized regulation of the systemic integrin-FAK pathway.

Normal vascular structure and function are crucial for the homeostasis of the central nervous system (CNS), yet the regulation of CNS vasculature remains incompletely understood. Here we show that CD98 heavy chain (CD98hc), also known as SLC3A2 or 4F2hc, is essential for CNS angiogenesis and blood-brain barrier (BBB) integrity. CD98hc is selectively enriched in the CNS endothelium versus the peripheral endothelium in mice and humans. Ablation of endothelial CD98hc in mouse embryos leads to aberrant CNS angiogenesis, impaired BBB formation and cerebral hemorrhage, without affecting the peripheral vasculature. In adults, endothelial CD98hc deficiency does not impact homeostatic CNS angiogenesis but disrupts the BBB and causes neurological deficits. The mechanism involves a CNS-specific reduction in the systemic integrin-FAK pathway in endothelial cells, affecting subsequent VEGFR2 and Wnt-β-catenin pathways. Importantly, FAK activation fully rectifies the CNS vascular phenotype in CD98hc-deficient mice. These findings open promising avenues for CNS-specific vascular regulation and targeted therapy of cerebrovascular diseases.