The Translational Significance of the Neurovascular Unit

Abstract

The mammalian brain is supplied with blood by specialized vasculature that is structurally and functionally distinct from that of the periphery. A defining feature of this vasculature is a physical blood-brain barrier (BBB). The BBB separates blood components from the brain microenvironment, regulating the entry and exit of ions, nutrients, macromolecules, and energy metabolites. Over the last two decades, physiological studies of cerebral blood flow dynamics have demonstrated that substantial intercellular communication occurs between cells of the vasculature and the neurons and glia that abut the vasculature. These findings suggest that the BBB does not function independently, but as a module within the greater context of a multicellular neurovascular unit (NVU) that includes neurons, astrocytes, pericytes, and microglia as well as the blood vessels themselves. Here, we describe the roles of these NVU components as well as how they act in concert to modify cerebrovascular function and permeability in health and in select diseases.

Keywords: blood-brain barrier; brain; brain tumor; cerebrovasculature; glioblastoma; neurovascular unit; vascular endothelial growth factor (VEGF); vasculogenesis.

FIGURE 1.

Anatomical structure of the NVU. A, a schematic representation of a capillary cross-section within a single neurovascular unit demonstrates the following important features: 1) Specialized brain endothelial cells line cerebral vessels. 2) Tight junctions between endothelial cells restrict paracellular diffusion and effectively “seal” the vessels. 3) A continuous basal lamina/basement membrane encases endothelial cells. Pericytes are embedded within this matrix, situated between endothelial cells and astroglial endfeet. 4) Astrocytes are centrally positioned within the brain parenchyma. These cells extend processes that communicate with local neurons and synapses and also extend foot-like processes that encase cerebral vessels. Astrocytes are therefore ideally localized to sense and respond to both neuronal and vascular activity. 5) Resident microglia use long cellular processes to survey their microenvironment and can quickly respond to insults at or near the NVU. 6) Local interneurons innervate cerebral vasculature and can induce vessels to change their tone based on incoming neuronal afferent signals (28) (adapted with permission from Macmillan Publishers Ltd.: Abbott et al. (2006) Nat. Rev. Neurosci. 7, 41–53 (97), © Macmillan Publishers Ltd.). B, electron micrograph of a capillary cross-section in rat brain. C, 3D reconstruction of immunofluorescent NVU images taken on a confocal microscope demonstrating von Willebrand Factor reactivity (endothelial cells) and glial fibrillary acidic protein reactivity (astrocytes) outside the vascular wall (panels B and C reprinted from Weiss et al. (2009) Biochim. Biophys. Acta 1788, 842–857 (98), with permission from Elsevier, © Elsevier).

FIGURE 2.

Perivascular clearance in brain: the glymphatic system. A, the glymphatic system consists of directional fluid flux along the abluminal surface of brain endothelium (black arrows) beneath astrocyte endfeet, which express high levels of the water channel aquaporin 4 (AQP-4). Convective movement of extracellular fluids and solutes helps drive clearance in the brain parenchyma, with drainage (at least in part) into the perivascular space (adapted from Iliff et al. (2015) Lancet Neurol. 14, 977–979 (99), with permission from Elsevier, © Elsevier). B, perivascular Virchow-Robin spaces may be demonstrable using MRI. A T2*-weighted MRI image shows decreased signal along penetrating arterioles in the cortex 2 h after an intrathecal cisternal injection of an iron oxide contrast agent (E. A. Neuwelt, unpublished pilot data).

FIGURE 3.

Neurovascular unit components act in concert to regulate cerebral blood flow. Glutamate is released during increased neuronal activity and binds receptors on astrocytes and neurons, inducing rises in intracellular calcium (Ca²⁺) levels. Ca²⁺ activates precursors that stimulate release of vasoactive mediators that induce cerebral vessels to constrict or dilate after binding their vascular receptors. This concerted activity between neurovascular unit components allows precise regulation of vasomotor responses to effect delivery of oxygen and glucose to brain regions with increased neuronal activity (adapted with permission from Macmillan Publishers Ltd.: Attwell et al. 2010 Nature 468, 232–243 (43), © Macmillan Publishers Ltd.; and from The American Physiological Society: Hamel et al. (2006) (100) J. Appl. Physiol. 100, 1059–1064, © The American Physiological Society).

FIGURE 4.

Antiangiogenic therapy normalizes tumor vasculature. A, normal capillary bed demonstrating typical physical interactions between arterial and venous circulation. B, tumor-secreted angiogenic factors induce neovascularization, resulting in abnormally tortuous and leaky vascular beds. Blood flow through these capillaries is decreased and inconsistent, possibly resulting in tissue hypoxia. C, treatment with anti-angiogenic therapy, such as the VEGF inhibitor bevacizumab, normalizes vascular beds and reduces their permeability (adapted with permission from Macmillan Publishers Ltd.: Farnsworth et al. 2014 Oncogene 33, 3496–3505 (76), © Macmillan Publishers Ltd.). D, once vascular beds are normalized with bevacizumab treatment, MRI-derived K^trans measurements of vascular permeability correlate linearly with the concentration of 2-[¹⁴C]aminoisobutyric acid (¹⁴C-AIB), a tracer with unidirectional permeability across the blood-brain barrier (adapted with permission from Biomed Central: Pishko et al. (2015) Fluids Barriers CNS 12, 5 (81), © Biomed Central).