Single-cell transcriptomic profiling reveals distinct vascular-associated microglia signatures in cerebral small vessel disease

Abstract

Cerebral small vessel disease (CSVD) is a major cause of cognitive impairment, characterized by neuroinflammation and microvascular dysfunction. A specialized subset of microglia, known as vascular-associated microglia (VAM), intimately interacts with the cerebral vasculature and plays a pivotal role in mediating neuroinflammation originating from the vasculature. However, the phenotypic changes of microglia in CSVD, particularly VAM subsets, and their crosstalk with microvascular cells remain largely unknown. Using single-cell RNA sequencing (scRNA-seq) on isolated cerebral microvessels from the renal hypertension rat (RHR) model of CSVD, we identified an increased proportion of VAM that is distinct from perivascular macrophages. Critically, a novel Spp1+ VAM subset emerged in the RHR model, exhibiting enhanced phagocytic, adhesive, and anti-inflammatory profiles. CellChat analysis further highlighted intensified VAM-endothelial interactions. Morphological changes and low proliferation rate suggested that VAM expansion arises from the recruitment of parenchymal microglia rather than in situ proliferation. These findings position the Spp1+ VAM subset as a key modulator of CSVD neuroinflammation. Targeting VAM recruitment and activation represents a promising therapeutic strategy to mitigate microvascular dysfunction and cognitive decline in CSVD.