Updated Understanding of the Glial-Vascular Unit in Central Nervous System Disorders

Abstract

The concept of the glial-vascular unit (GVU) was raised recently to emphasize the close associations between brain cells and cerebral vessels, and their coordinated reactions to diverse neurological insults from a "glio-centric" view. GVU is a multicellular structure composed of glial cells, perivascular cells, and perivascular space. Each component is closely linked, collectively forming the GVU. The central roles of glial and perivascular cells and their multi-level interconnections in the GVU under normal conditions and in central nervous system (CNS) disorders have not been elucidated in detail. Here, we comprehensively review the intensive interactions between glial cells and perivascular cells in the niche of perivascular space, which take part in the modulation of cerebral blood flow and angiogenesis, formation of the blood-brain barrier, and clearance of neurotoxic wastes. Next, we discuss dysfunctions of the GVU in various neurological diseases, including ischemic stroke, spinal cord injury, Alzheimer's disease, and major depression disorder. In addition, we highlight the possible therapies targeting the GVU, which may have potential clinical applications.

Keywords: Alzheimer’s disease; Blood-brain barrier; Glial-vascular unit; Glymphatic system; Ischemic stroke; Major depression disorder; Perivascular space; Spinal cord injury.

Fig. 1

Schematic of the PVS in the GVU at the level of a penetrating artery and capillary. A The PVS around a penetrating artery is surrounded by astrocytic endfeet, and the inner side of the PVS is composed of vascular ECs and vascular basement membrane including SMCs. PVMs locate in the PVS, and CSF flows in the PVS from where it is transported into the parenchyma by AQP4 expressed on astrocytic endfeet, forming the glymphatic system. B At the level of capillaries, pericytes rather than PVMs locate in the PVS. Basement membrane and astrocytic endfeet gradually fuse, so the PVS finally diminishes and forms a blind end.

Fig. 2

Schematic of the GVU functional network. The GVU is composed of glial cells including astrocytes and microglia, and perivascular cells including ECs, pericytes, and PVMs. The crosstalk of glial cells and perivascular cells in the PVS niche contributes to the successful fulfilment of diverse functions including the modulation of CBF and angiogenesis, the maintenance of BBB integrity, and the elimination of neurotoxic waste-products via the glymphatic system.

Fig. 3

Comparison of the GVU under physiological and pathological conditions. The individual components of the GVU work in concert to execute normal functions under physiological conditions (e.g., tripartite synapses). To facilitate glial-neuronal-vascular transport and signal transduction, microglia maintain CNS homeostasis by phagocytosis and immune modulation, pericytes cover the capillary surface to modulate CBF, and the PVS and PVMs participate in the brain-waste clearance system). Under pathological conditions, responses to stimuli have been reported, including neuronal death and synapse degeneration, gliosis, release of inflammatory chemokines, BBB leakage, and impaired waste clearance.