Introduction to the neurovascular unit

Abstract

For many years, a neurocentric view toward mechanisms of ischemic brain injury and repair has significantly contributed to our knowledge of the molecular pathways of excitotoxicity, oxidative stress and apoptosis. However, translation of these laboratory results into clinically effective stroke treatments remains a major challenge. To address this issue and the prediction that strokes will increase in our aging population, the U.S. Congress requested the National Institute of Neurological Disorders and Stroke (NINDS) to develop a stroke research action plan through the Stroke Progress Review Group (SPRG). The SPRG identified research on the cellular and functional interactions among the capillaries, glia, and neurons of the brain, termed the unit (NVU), as a top priority. The NVU strategy looks beyond the single cell for a more integrative answer to ischemic brain damage which may be closer to modeling the clinical reality. The NVU construct is intended to facilitate a better understanding of the integration of cerebrovascular and neurobiological mechanisms in the development of the healthy brain, in the maintenance of function in the aging brain, and in neurological disorders and stroke. A major goal is to improve our knowledge of cell-cell communication within the NVU and how vascular function may contribute to the initiation and/or progression of neurological diseases over the lifespan. The NVU concept focuses attention on the interactions among cells of the brain and blood vessels and includes the endothelium, extracellular matrix, glia, pericytes and neurons. After ischemia, perturbations in neurovascular functional integrity initiate several cascades of injury. Neuronal cell death ultimately underlies ischemic brain injury and the NVU concept suggests that proximal triggers in endothelium play an important upstream role. For example, signals such as oxidative stress, together with neutrophil and/or platelet interactions with activated endothelium, upregulate matrix metalloproteinases, plasminogen activators and other proteases, which degrade matrix and lead to blood–brain barrier leakage. Disruption of cell-matrix homeostasis might also trigger cell death pathways in both vascular and parenchymal compartments. Refocusing research on how endothelial injury affects brain tissue damage applies not only to stroke, but may also contribute to understanding neurodegenerative disorders, like vascular dementia, Alzheimer's disease, MS and ALS, in which vascular changes are observed. Thrombolysis trials firmly establish the idea that timely reperfusion can salvage the ischemic brain. The efficacy of hypothermia so far confirms that multiple molecular cascades are indeed operational in human brain and that neuroprotection is an achievable goal. Ultimately, new approaches for targeting the NVU, based on biological considerations, could be developed to improve potential combination or multi-targeted treatments for stroke and other neurological disorders.