The Endothelial Cell-Expressed Prion Protein Prnd/Doppel Promotes Neovascularization and Long-term Recovery after Ischemic Stroke

Ischemic stroke remains a leading cause of mortality and long-term disability, yet therapeutic options for promoting recovery remain severely limited. Here, we investigate the role of Prnd/Doppel, a prion family member, in stroke pathophysiology and recovery. Using middle cerebral artery occlusion (MCAO) in mice genetically null for Prnd (KO), inducibly overexpressing Prnd in endothelial cells (ECs), or wild-type (WT) controls, we assessed outcomes through infarct volume measurements, behavioral analysis, and immunohistochemical evaluation of vascular integrity and inflammation. While acute infarct volumes at 24 hours were comparable between WT and KO mice, striking differences emerged during recovery: KO mice exhibited significantly impaired functional outcomes at both 14 and 30 days post-MCAO, accompanied by disorganized cerebrovascular architecture, increased brain atrophy, and elevated CD68-positive inflammatory infiltration by day 30. Conversely, endothelial-specific Prnd overexpression, though not affecting acute outcomes, markedly enhanced tight junction protein expression at day 7, promoted angiogenesis, and improved long-term neuronal survival in the ischemic territory. These findings establish Prnd as a critical mediator of post-stroke vascular remodeling and functional recovery, distinguishing it from acute neuroprotective mechanisms. Our results identify Prnd as a promising therapeutic target for enhancing organized neovascularization and promoting sustained functional recovery following ischemic stroke, with potential applications to other neurological disorders characterized by cerebrovascular dysfunction.