Neurovascular Unit Dysfunction in Ischemic Stroke: Cellular and Molecular Mechanisms and Therapeutic Implications

Ischemic stroke represents a complex and devastating neurological disorder characterized by acute cerebral blood flow reduction, extensive neuronal injury, and multifaceted vascular and inflammatory alterations. The pathophysiology of ischemic stroke extends far beyond neuronal damage and critically involves dysfunction of the neurovascular unit (NVU). The NVU is recognized as a dynamic complex comprising Endothelial cells (ECs), the basement membrane (BM), pericytes, astrocytes, microglia, and ultimately neurons. It plays a fundamental role in maintaining cerebral blood flow (CBF) and blood–brain barrier (BBB) integrity. Disruption of NVU homeostasis contributes to microcirculatory impairment and BBB breakdown, thereby exacerbating ischemic outcomes. Increasing evidence indicates that NVU dysfunction is not merely a consequence of ischemia but an active driver of stroke progression and neurological deterioration. However, the precise molecular mechanisms underlying NVU impairment and its stage-specific contributions to ischemic injury remain incompletely understood. This review highlights how NVU disruption regulates the progression of ischemic stroke and summarizes the potential cellular and molecular mechanisms involved in NVU dysfunction. Moreover, emerging therapeutic strategies targeting NVU protection and restoration are discussed as promising approaches to complement reperfusion therapies and improve stroke outcomes. Ischemic stroke represents a systems-level failure of the neurovascular unit. Chronic comorbidities and systemic physiological factors increase NVU vulnerability, while ischemia-induced inflammatory, oxidative, thrombo-inflammatory, and matrix-remodeling cascades drive neurovascular dysfunction. Multi-target therapeutic strategies aimed at preserving NVU integrity may improve stroke outcomes.