Neurovascular unit remodeling: focusing on glial cells in stroke injury and recovery

Stroke stands as a predominant global contributor to mortality and persistent disability, marked by a sequential cascade of pathophysiological perturbations. Moving beyond the traditional neuron-focused paradigm, contemporary stroke research has increasingly centered on the neurovascular unit (NVU), a functional multicellular assembly encompassing neurons, glial cells, and cerebrovascular components, as the pivotal regulatory hub for cerebral homeostasis and adaptive responses to injury. Among NVU components, glial cells are no longer viewed as passive supporters but as active regulators of NVU integrity, blood-brain barrier (BBB) functionality, immune surveillance, and tissue repair processes. Stroke trigger distinct spatiotemporal phenotypic changes in glial cells. Microglia show biphasic pro-inflammatory and pro-repair polarization. Astrocytes undergo reactive gliosis and form glial scars with dual functions. Oligodendrocytes experience iron-related or ischemic injury and contribute to remyelination. Hypertension, hyperglycemia and aging jointly induce glial dysfunction and predispose the NVU to a pre-vulnerable state that worsens post-stroke damage. This review emphasizes the multifaceted roles of glia-mediated NVU remodeling in stroke injury and recovery, addresses the modulatory effects of comorbid risk factors on glial functions and explores glia-targeted therapeutic strategies that hold promise for preserving NVU function and improving stroke outcomes.