Endothelial Cell-Expressed Prion Protein Prnd/Doppel Promotes Long-Term Recovery After Ischemic Stroke

BACKGROUND: Recovery after ischemic stroke is limited by persistent cerebrovascular dysfunction, but the mechanisms regulating vascular repair remain poorly understood. Prnd (Prnd/Doppel) is a prion family protein expressed in the cerebrovascular endothelium during development. We tested the hypothesis that endothelial Prnd promotes vascular repair and functional recovery in the adult brain after stroke. METHODS: Using middle cerebral artery occlusion in mice, we compared wild-type and Prnd-null mice and evaluated endothelial-specific Prnd overexpression. Functional recovery was assessed by behavioral testing, while infarct volume, brain atrophy, vascular architecture, blood-brain barrier integrity, and macrophage/microglia infiltration were evaluated histologically. Vascular signaling and endothelial cell junctional proteins were examined mechanistically. RESULTS: Acute infarct volumes were comparable between wild-type and Prnd-null mice, indicating that Prnd does not substantially affect initial ischemic injury. During recovery, however, Prnd-null mice exhibited disrupted cerebrovascular architecture, increased blood-brain barrier disruption, greater brain atrophy, and increased macrophage/microglial infiltration. Conversely, endothelial Prnd overexpression improved long-term functional recovery without altering acute infarct size and was associated with enhanced blood-brain barrier integrity and vascular remodeling. Mechanistically, Prnd manipulation was associated with enhanced VEGF-A (vascular endothelial growth factor-A) signaling and increased endothelial cell tight junction protein expression. CONCLUSIONS: Prnd is dispensable for acute ischemic injury but promotes cerebrovascular remodeling, blood-brain barrier restoration, and functional recovery after stroke. These findings identify endothelial Prnd as a regulator of poststroke vascular repair and a potential therapeutic target for enhancing long-term recovery.