Biphasic mechanisms of neurovascular unit injury and protection in CNS diseases

Abstract

In the past decade, evidence has emerged that there is a variety of bidirectional cell-cell and/or cell-extracellular matrix interactions within the neurovascular unit (NVU), which is composed of neuronal, glial, and vascular cells along with extracellular matrix. Many central nervous system diseases, which lead to NVU dysfunction, have common features such as glial activation/transformation and vascular/blood-brain-barrier alteration. These phenomena show dual opposite roles, harmful at acute phase and beneficial at chronic phase. This diverse heterogeneity may induce biphasic clinical courses, i.e. degenerative and regenerative processes in the context of dynamically coordinated cellcell/ cell-matrix interactions in the NVU. A deeper understanding of the seemingly contradictory actions in cellular levels is essential for NVU protection or regeneration to suppress the deleterious inflammatory reactions and promote adaptive remodeling after central nervous system injury. This mini-review will present an overview of recent progress in the biphasic roles of the NVU and discuss the clinical relevance of NVU responses associated with central nervous system diseases, such as stroke and other chronic neurodegenerative diseases.

Figure 1

Schematic of the Neurovascular Unit. Neuron, astrocyte, cerebral endothelium, oligodendrocyte, microglia, and pericyte compose the neurovascular unit (NVU), and cell-cell interactions between the NVU components may maintain the brain homeostasis. BBB: blood-brain barrier

Figure 2

Schematic to summarize the biphasic responses after stroke onset. In the acute phase, deleterious responses occur. On the other hand, remodeling signaling may emerge at the later time point. Interestingly, NVU mediators such as HMGB-1 would work in both phases, with opposite actions. NVU: neurovascular unit, BBB: blood-brain barrier

Figure 3

Schematic to summarize the pathologic processes in CNS diseases. In most cases of CNS diseases, glial activation, vascular alteration, and inflammatory reaction are observed after the onset of stress. These responses lead to brain injury at the acute phase, but may contribute to neurovascular remodeling in the chronic phase. BBB: blood-brain barrier