Central integration mechanisms of neurovascular unit dysfunction and novel synergistic therapeutic strategies

The neurovascular unit (NVU) is a highly integrated multicellular complex composed of neurons, astrocytes, microglia, brain microvascular endothelial cells (BMECs), pericytes, and the extracellular matrix (ECM). It forms the structural and functional basis of the blood-brain barrier (BBB) and is pivotal for maintaining the homeostasis of the brain. Traditional neuroprotective strategies targeting individual cell types have shown limited efficacy in central nervous system (CNS) diseases, mainly due to the neglect of intricate intercellular crosstalk within the NVU. In this review, we first systematically summarize the core mechanisms by which the NVU functional unit causes NVU dysfunction in representative acute CNS injuries (ischemic/hemorrhagic stroke, traumatic brain injury), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, multiple sclerosis), and systemic diseases (diabetic encephalopathy, depression). Based on this, we innovatively summarize and clarify six major cross-disease pathological mechanisms of NVU dysfunction, including intercellular communication disorders, abnormal epigenetic modifications, microbiome-NVU interaction dysregulation, metabolic reprogramming dysfunction, neuroimmune-vascular coupling imbalance, and mechanical microenvironment imbalance. Additionally, we integrate emerging NVU models (co-culture systems, organoids, microfluidic chips, 3D bioprinting) with multi-omics technologies to establish a cross-scale dynamic research paradigm, and propose multicomponent coordinated regulatory strategies for NVU-targeted therapies. This framework aims to expand the understanding of NVU-centered pathological processes across diverse CNS diseases and provides a novel theoretical basis for precise therapeutic interventions, thereby bridging the gap between basic research and clinical translation.