The Translational Significance of the Neurovascular Unit
2016; Elsevier BV; Volume: 292; Issue: 3 Linguagem: Inglês
10.1074/jbc.r116.760215
ISSN1083-351X
AutoresHeather McConnell, Cymon Kersch, Randall L. Woltjer, Edward A. Neuwelt,
Tópico(s)Cerebrospinal fluid and hydrocephalus
ResumoThe 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. 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. The neurovascular unit (NVU) 2The abbreviations used are: NVUneurovascular unitECendothelial cellBBBblood-brain barrierTJtight junctionCBFcerebral blood flowECMextracellular matrixAAarachidonic acid20-HETE20hydroxyeicosatetraenoic acidEETepoxyeicosatrienoic acidADAlzheimer's diseaseAPPamyloid precursor proteinAβamyloid β. enables tight regulation of blood flow through the vasculature, which has unique structure in the brain. The arteries that dive into the brain from the subarachnoid space consist of endothelial cells (ECs), a basement membrane, smooth muscle cells, the perivascular (Virchow-Robin) space, pia mater, and astrocyte endfeet (see FIGURE 1, FIGURE 2). As vessels continue deeper into the brain, they lose their smooth muscle cell and pia mater coverage, gaining pericytes between the EC and astrocyte endfeet. Along the length of the cerebral vasculature, neuronal and astrocyte processes contact other components of the NVU, where they can influence the function of the entire unit. Here we describe individual NVU components and their roles within the NVU.FIGURE 2Perivascular 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 (99Iliff J.J. Goldman S.A. Nedergaard M. Implications of the discovery of brain lymphatic pathways.Lancet Neurol. 2015; 14: 977-979Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar), 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).View Large Image Figure ViewerDownload Hi-res image Download (PPT) neurovascular unit endothelial cell blood-brain barrier tight junction cerebral blood flow extracellular matrix arachidonic acid 20hydroxyeicosatetraenoic acid epoxyeicosatrienoic acid Alzheimer's disease amyloid precursor protein amyloid β. The ECs lining cerebral blood vessels are the core anatomical unit of the vascular blood-brain barrier (BBB), protecting the brain from systemic influences by limiting transcellular and paracellular transport mechanisms. Brain vascular ECs contain no fenestrae and undergo very low rates of transcytosis (1Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer's disease.Nat. Rev. Neurosci. 2004; 5: 347-360Crossref PubMed Scopus (1706) Google Scholar). Tight junctions (TJs) and adherens junctions formed between adjacent ECs underlie the physical barrier that impedes paracellular diffusion of ions, macromolecules, and other polar solutes (Fig. 1, A and B). Structurally, TJs are composed of combinations of integral membrane proteins including occludins and claudins (which form dimers with their counterparts on adjacent ECs) and cytoplasmic proteins that couple these transmembrane proteins to the actin cytoskeleton (2Stamatovic S.M. Keep R.F. Andjelkovic A.V. Brain endothelial cell-cell junctions: how to "open" the blood brain barrier.Curr. Neuropharmacol. 2008; 6: 179-192Crossref PubMed Scopus (362) Google Scholar). The result is a tight interendothelial seal with in vivo transendothelial electrical resistances of up to 1800 ohms/cm2 (3Butt A.M. Jones H.C. Abbott N.J. Electrical resistance across the blood-brain barrier in anaesthetized rats: a developmental study.J. 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Brain endothelial cell-cell junctions: how to "open" the blood brain barrier.Curr. Neuropharmacol. 2008; 6: 179-192Crossref PubMed Scopus (362) Google Scholar). The specialization of brain vascular ECs reflects the unique requirements of an organ that demands a homeostatic ionic environment and protection from neuroactive blood-borne solutes. Pericytes are mural cells embedded within the basement membrane that envelops blood vessels. Pericytes extend thin processes around and along pre-capillary arterioles, capillaries, and post-capillary venules (Fig. 1, A and B) (5Sweeney M.D. Ayyadurai S. Zlokovic B.V. Pericytes of the neurovascular unit: key functions and signaling pathways.Nat. Neurosci. 2016; 19: 771-783Crossref PubMed Scopus (560) Google Scholar). 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Secreted proteins make up a specialized extracellular matrix (ECM) that forms the basement membrane between ECs and pericytes and between astrocytes and pericytes (Fig. 1A). Pericyte coverage of vasculature is discontinuous; in areas of discontinuity, a single basement membrane is shared between astrocytes and ECs. Proteomic studies from rodent vasculature demonstrate that the brain vasculature ECM protein composition differs from that present in the periphery. Even within the brain, basement membrane protein composition varies greatly between large and small vessels (32Joutel A. Haddad I. Ratelade J. Nelson M.T. Perturbations of the cerebrovascular matrisome: a convergent mechanism in small vessel disease of the brain?.J. Cereb. Blood Flow Metab. 2016; 36: 143-157Crossref PubMed Scopus (62) Google Scholar), providing evidence that the NVU is functionally heterogeneous throughout the brain. Key proteins of the basement membranes include numerous isoforms of ECM proteins such as collagens, fibrillins, laminins, vitronectin, and fibronectin as well as soluble factors (e.g. growth factors and cytokines), enzymes responsible for matrix degradation and processing (including matrix metalloproteases), and proteins known to bind to ECM (e.g. lectins and semaphorins). Both ECM and support protein components of the basement membrane are essential to proper NVU functioning as they directly mediate the activation state of many receptors on the cellular components of this unit. Dysfunction and degradation of the basement membrane are associated with several CNS disease states. Microglia are the primary immune cells of the brain. Early in development, these yolk sac-derived myeloid precursors seed the brain (33da Fonseca A.C. Matias D. Garcia C. Amaral R. Geraldo L.H. Freitas C. Lima F.R. The impact of microglial activation on blood-brain barrier in brain diseases.Front. Cell. 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Temporal and spatial orchestration of increased blood flow to CNS tissue in response to neural activity is termed functional hyperemia (1Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer's disease.Nat. Rev. Neurosci. 2004; 5: 347-360Crossref PubMed Scopus (1706) Google Scholar). To effect the delivery of blood substrates such as oxygen and glucose to metabolically active regions of the brain, local groups of neurons and their associated astrocytes signal to smooth muscle cells or pericytes and vascular ECs to modify vascular tone. Although neurons are able to contact and signal to the vasculature directly, astrocytes can act as relays between neurons and ECs (43Attwell D. Buchan A.M. Charpak S. Lauritzen M. Macvicar B.A. Newman E.A. Glial and neuronal control of brain blood flow.Nature. 2010; 468: 232-243Crossref PubMed Scopus (1612) Google Scholar). 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