The Molecular Neurobiology of NG2-Expressing Glial Cells in Cerebral Small Vessel Disease Pathogenesis.

Cerebral small vessel disease (CSVD) is a major contributor to stroke and vascular cognitive impairment, yet effective disease-modifying treatments remain lacking. Emerging evidence suggests that neuro-glial-vascular interactions play a pivotal role in the pathogenesis of CSVD. Among glial populations, neuron-glia antigen 2 (NG2)-expressing glial cells, also known as polydendrocytes or oligodendrocyte precursor cells, are increasingly recognized as dynamic regulators of neurovascular integrity, immune signaling, and white matter repair. Traditionally viewed as progenitors for myelinating oligodendrocytes, NG2 glia also form synaptic contacts with neurons, associate with blood vessels, and engage in bidirectional crosstalk with astrocytes, microglia, endothelial cells, and pericytes. These properties enable them to influence blood-brain barrier (BBB) stability, angiogenesis, inflammatory polarization, and remyelination, processes directly implicated in the development and progression of CSVD. This narrative review synthesizes current knowledge on NG2 glial cells neurobiology with a focus on molecular mechanisms relevant to CSVD, including hypoxia-driven signaling, extracellular matrix remodeling, and context-dependent differentiation. This review also highlights translational opportunities, such as targeting inhibitory pathways, modulating trophic interactions with microglia, and leveraging NG2-mediated vascular support to promote repair. By reframing CSVD through the lens of NG2 glial function, this review provides a mechanistic framework that positions NG2 glia as one of the central orchestrators of neurovascular health and identifies them as promising targets for therapeutic intervention in a disease of high societal and clinical burden.