Astrocytic VPS35 coordinates iron homeostasis with HIF1α-VEGFa signaling to prevent astrocytic ferroptosis and to promote neocortical angiogenesis.

Astrocytes coordinate neuronal activity with vascular development and metabolic homeostasis during postnatal brain maturation, yet the mechanisms enabling astrocytes to support angiogenesis remain elusive. VPS35, a core component of the retromer complex, regulates transmembrane protein trafficking and is implicated in multiple neurodegenerative diseases; however, its function in astrocytes is unknown. Here, we identify astrocytic VPS35 as a crucial regulator for astrocyte maturation and neurovascular development through its control of iron homeostasis and HIF1α-VEGFa signaling. Conditional deletion of Vps35 in astrocytes impaired astrocyte maturation and survival, as well as basal and activity-dependent angiogenesis, thus reducing cerebral blood flow, and inducing widespread vascular abnormalities in both cortical and meningeal vessels. Mechanistically, loss of astrocytic Vps35 resulted in intracellular iron accumulation, likely due to impaired ferroportin (FPN)-mediated iron export. Iron overload enhanced HIF1α hydroxylation and degradation, suppressing VEGFa expression and attenuating angiogenic responses. In parallel, excess iron induced astrocyte ferroptosis, characterized by increased lipid peroxidation, diminished antioxidant capacity, astrocyte loss, and impaired astrocyte maturation. Importantly, iron chelation reduced ferroptotic stress, restored HIF1α-VEGFa signaling, and rescued vascular density in mutant mice. Together, these findings establish astrocytic VPS35 as a critical integrator of endosomal protein trafficking, iron metabolism, and angiogenic signaling, and identify iron dysregulation as a central mechanism linking retromer dysfunction to impaired astrocyte and neurovascular development.