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

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.

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.

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.

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.