Endothelial Cell-Pericyte Interplay in Ischemic Stroke: Unraveling Pathogenic Networks and Translational Frontiers

Abstract

Ischemic stroke remains a leading cause of death and long-term disability worldwide. Increasing evidence indicates that endothelial cell-pericyte (EC-PC) crosstalk is not merely a structural feature of the neurovascular unit, but a dynamic regulatory axis that shapes blood-brain barrier integrity, capillary tone, inflammatory trafficking, and vascular repair after ischemia. In this review, we synthesize current evidence into a stage-aware framework in which EC-PC communication shifts from homeostatic coupling to acute uncoupling, maladaptive remodeling, and, in favorable settings, reparative re-coupling. We summarize the principal molecular pathways governing this interaction, including PDGF, TGF-β, Notch, extracellular matrix signaling, exosomal communication, and adhesion-dependent mechanotransduction. We further discuss how disruption of this axis contributes to blood-brain barrier breakdown, inflammatory amplification, oxidative injury, aberrant angiogenesis, and impaired neurorestoration. Finally, we evaluate the translational implications of EC-PC crosstalk for biomarker discovery, imaging-based assessment, and targeted intervention, while highlighting key unresolved issues—particularly temporal heterogeneity, context-dependent signaling, and the gap between experimental models and human stroke—that must be addressed to move the field toward clinically actionable neurovascular therapies.