Microglia promote vascular remodeling in a mouse model of chronic stress

Major Depressive Disorder (MDD) is a debilitating mental illness affecting over 350 million people globally. Chronic stress is a major risk factor for MDD and is associated with increased vascular dysfunction and cardiovascular disease. While inflammation is often implicated in these pathologies, the specific interactions between immune cells and the cerebral vasculature in the context of chronic stress remain poorly understood. We employed a chronic social defeat stress (CSDS) model in mice to investigate immune-vascular interactions in the medial prefrontal cortex (mPFC). We also used a subthreshold stress model to assess the temporal sequence of microglial and vascular changes. To explore the role of endothelial signaling, we utilized a CD31 knockout model. Microglial activation, vascular morphology, and immune cell infiltration were assessed using immunohistochemistry and functional assays. Chronic stress induced microglial activation and increased microglia-vessel interactions in the mPFC, which were associated with impaired vascular morphology. These interactions were observed to precede vascular changes in the subthreshold model. Cytokines released by interferon (IFN)γ-stimulated microglia promoted macrophage infiltration into the brain. Deletion of endothelial CD31, a key mediator of transendothelial migration, prevented macrophage recruitment and protected against inflammatory, vascular, and behavioral deficits associated with CSDS. Our findings highlight important immune-vascular interactions in chronic stress, where microglia contribute to cerebrovascular remodeling and facilitate macrophage infiltration via CD31-dependent pathways. These interactions may underlie the pathophysiology of MDD and its vascular comorbidities, offering potential therapeutic targets.