Pathophysiological Role of Perivascular Macrophages in Blood–Brain Barrier Dysfunction Induced by Cerebral Hypoperfusion in Mice

Abstract

This study investigated the role of perivascular macrophages (PVMs), localized alongside the brain vasculature, in blood-brain barrier (BBB) dysfunction induced by reduced cerebral blood flow (CBF). Using a mouse model of bilateral carotid artery stenosis (BCAS) to examine cerebral hypoperfusion, the effects of pharmacological depletion of PVM-enriched macrophage populations were examined using clodronate liposomes. The results demonstrated that while cerebral hypoperfusion significantly increased BBB permeability, depletion of PVM-enriched macrophage populations attenuated this leakage. Mechanistic analyses suggested that PVM-associated responses may be linked to reduced pericyte marker expression, astrocyte activation, and increased MMP-2/9 expression. Furthermore, depletion of PVM-enriched macrophage populations inhibited the upregulation of matrix metalloproteinase-2 (MMP-2) and MMP-9. These findings suggest that PVM-enriched macrophage populations are involved in early BBB dysfunction following cerebral hypoperfusion, possibly through changes in pericyte-associated vascular integrity, astrocyte activation, and MMP-2/9-related tight junction remodeling. These results provide insight into vascular inflammatory mechanisms that may contribute to hypoperfusion-associated BBB dysfunction and later small vessel pathology.