Pericyte Loss Reprogrammes Capillary Endothelium and Drives White Matter Injury in Small Vessel Disease

Abstract Pericytes are critical regulators of cerebrovascular homeostasis, yet their contribution to small vessel disease (SVD) and white matter injury remains incompletely understood. Here, we use an inducible Atp13a5 -driven genetic strategy to selectively label and ablate brain pericytes, enabling integrated morphological, functional, and transcriptomic analyses across the neurogliovascular unit. Single-cell RNA sequencing and tissue-level mapping identified distinct pericyte subtypes distributed along the vascular tree and revealed subtype-specific vulnerability following depletion. Moderate pericyte loss induced transient cerebrovascular dysfunction characterised by reduced cerebral blood flow and increased blood-brain barrier (BBB) permeability, accompanied by delayed white matter abnormalities, including altered diffusion MRI metrics, oligodendrocyte progenitor cell responses, and myelin loss. At the molecular level, pericyte depletion reprogrammed capillary endothelial cells toward an activated venular-like state characterised by VCAM-1 induction, reduced expression of the BBB-associated transporter MFSD2A, and activation of type I interferon signalling pathways. Cross-species analyses revealed enrichment of human white matter hyperintensity-associated SVD gene signatures across endothelial subtypes following pericyte depletion. Together, these findings identify pericyte dysfunction as a driver of endothelial inflammatory remodelling and white matter injury and establish mechanistic links between microvascular pericyte loss and human SVD.