Time-dependent neurovascular unit dysfunction in ischemic stroke: mechanisms of neurovascular uncoupling and its clinical impact

AIM: Neurovascular unit (NVU) dysfunction is a central determinant of tissue injury, reperfusion failure, and long-term neurological outcomes after ischemic stroke. This review critically examines the cellular and molecular mechanisms underlying NVU disruption, with a particular focus on inflammation, oxidative stress and blood-brain barrier (BBB) integrity, and evaluates emerging NVU-targeted therapeutic strategies. METHODS: A focused narrative review synthesized studies on ischemic stroke-related NVU alterations, integrating cellular mechanisms, biomarkers and phase-specific therapeutic strategies targeting BBB dysfunction, inflammation, oxidative stress and neurorestoration. RESULTS: Acute ischemic injury induces endothelial tight-junction disruption, pericyte constriction and loss, astrocytic activation and microglial-driven inflammation, resulting in BBB breakdown, impaired neurovascular coupling (NVC) and restricted microvascular reperfusion. These processes facilitate leukocyte infiltration, exacerbate secondary neuronal damage and increase hemorrhagic transformation risk. Circulating and cerebrospinal fluid (CSF) biomarkers, including MMP-9, GFAP, S100B and pro-inflammatory cytokines, reflect NVU injury severity and correlate with functional outcomes. In the chronic phase, persistent BBB permeability, maladaptive VEGF signaling and sustained low-grade inflammation contribute to white matter injury, impaired neuroplasticity and post-stroke cognitive decline. Therapeutic strategies targeting NVU dysfunction include anti-inflammatory agents, COX-2 inhibitors and NADPH oxidase (NOX) inhibitors, alongside stem cell-based and extracellular vesicle-mediated approaches that promote vascular stabilization and repair. Neuroplasticity-enhancing interventions and nanoparticle-based drug delivery systems further support functional recovery. CONCLUSIONS: NVU dysfunction underlies both acute injury amplification and chronic recovery failure after stroke. Biomarker-guided, phase-specific therapeutic strategies targeting inflammation, oxidative stress and BBB instability represent a promising framework for personalized stroke management.