Vascularización cerebral (parte I)

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Vascularización cerebral (parte I)

  1. 1. Vascularización cerebralmartes 15 de noviembre de 2011
  2. 2. Vascularización cerebral Enrike G. Argandoñamartes 15 de noviembre de 2011
  3. 3. Vascularización cerebral Enrike G. Argandoñamartes 15 de noviembre de 2011
  4. 4. Vascularización cerebral 2martes 15 de noviembre de 2011
  5. 5. Vascularización cerebral Sistema arterial aferente 2martes 15 de noviembre de 2011
  6. 6. Vascularización cerebral Sistema arterial aferente Sistema venoso eferente 2martes 15 de noviembre de 2011
  7. 7. Vascularización cerebral 3martes 15 de noviembre de 2011
  8. 8. Vascularización cerebral 1% volumen cerebral 3martes 15 de noviembre de 2011
  9. 9. Vascularización cerebral 1% volumen cerebral 20% Gasto cardiaco 3martes 15 de noviembre de 2011
  10. 10. Vascularización cerebral 1% volumen cerebral 20% Gasto cardiaco 25% consumo energía 3martes 15 de noviembre de 2011
  11. 11. martes 15 de noviembre de 2011
  12. 12. martes 15 de noviembre de 2011
  13. 13. Vascularización cerebral 5martes 15 de noviembre de 2011
  14. 14. Vascularización cerebral Control de la circulación sistémica 5martes 15 de noviembre de 2011
  15. 15. Vascularización cerebral Control de la circulación sistémica Autorregulación vascularización cerebral 5martes 15 de noviembre de 2011
  16. 16. Vascularización cerebral Control de la circulación sistémica Autorregulación vascularización cerebral Distribución del flujo 5martes 15 de noviembre de 2011
  17. 17. martes 15 de noviembre de 2011
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  25. 25. 14 Vascularización cerebralmartes 15 de noviembre de 2011
  26. 26. 14 Vascularización cerebralmartes 15 de noviembre de 2011
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  45. 45. Vascularización intracerebral 31martes 15 de noviembre de 2011
  46. 46. Vascularización intracerebral Arteriolas (50-100 µm) 31martes 15 de noviembre de 2011
  47. 47. Vascularización intracerebral Arteriolas (50-100 µm) Arteriolas terminales (10-100µm) 31martes 15 de noviembre de 2011
  48. 48. Vascularización intracerebral Arteriolas (50-100 µm) Arteriolas terminales (10-100µm) Vénulas (± 30 µm) 31martes 15 de noviembre de 2011
  49. 49. Vascularización intracerebral Arteriolas (50-100 µm) Arteriolas terminales (10-100µm) Vénulas (± 30 µm) Capilares (<30 µm) 31martes 15 de noviembre de 2011
  50. 50. Vascularización cortical Red capilar 640 km (reducida en Alzheimer) Un capilar por neurona Barrera hematoencefálica Mecanismos estructurales Mecanismos metabólicosmartes 15 de noviembre de 2011
  51. 51. Barreras cerebralesmartes 15 de noviembre de 2011
  52. 52. Barreras cerebralesmartes 15 de noviembre de 2011
  53. 53. 34 Barrera hematoencefálicamartes 15 de noviembre de 2011
  54. 54. 34 Barrera hematoencefálicamartes 15 de noviembre de 2011
  55. 55. 34 Barrera hematoencefálicamartes 15 de noviembre de 2011
  56. 56. 35 Barrera hematoencefálicamartes 15 de noviembre de 2011
  57. 57. 35 Barrera hematoencefálicamartes 15 de noviembre de 2011
  58. 58. Tipos de transporte Textomartes 15 de noviembre de 2011
  59. 59. a Tipos de transporte b c d e Paracellular aqueous Transcellular Transport proteins Receptor-mediated Adsorptive pathway lipophilic transcytosis transcytosis pathway Water-soluble Lipid-soluble Glucose, Vinca alkaloids, Insulin, Albumin, other agents agents amino acids, Cyclosporin A, transferrin plasma proteins nucleosides AZT +++ + + +++ Blood –––– + –+ + – + + –+ + – + Tight junction –+ + + – + + Texto –+ + + – – – Endothelium – – +++ Brain + + +++ Astrocyte Astrocyte Figure 3 | Pathways across the blood–brain barrier. A schematic diagram of the endothelial cells that form the blood– brain barrier (BBB) and their associations with the perivascular endfeet of astrocytes. The main routes for molecular traffic across the BBB are shown. a | Normally, the tight junctions severely restrict penetration of water-solublemartes 15 de noviembre de 2011
  60. 60. martes 15 de noviembre de 2011
  61. 61. at the BBB is observed in starvation and hypoxia53,54.Blood Ligand Tight junction Receptor ↑Ca2+ ↑Ca2+Endothelial cell Pericyte Smooth muscle Basal Microglia lamina Neuron Astrocyte NeuronFigure 5 | Complex cell–cell signalling at the blood–brain barrier. A portion of abrain capillary wall, showing the main cell types present with the potential to signal toeach other. Pericytes are enclosed within the endothelial basal lamina and form theclosest associations with endothelium. The endfeet of astrocytic glial cells are apposedmartes 15 de noviembre de 2011
  62. 62. Review Figure 3. A Simplified Molecular Atlas of the BBB (A) Tight junctions. Claudins (claudin-3, -5, and -12) and occludin have four transmembrane domains with two extracellular loops. The junctional adhesion m ecule A (JAM-A) and the endothelial cell-selective adhesion molecule (ESMA) are members of the Ig superfamily. Zonula occludens proteins (ZO-1, ZO-2, and ZO and the calcium-dependent serine protein kinase (CASK) are first-order cytoplasmic adaptor proteins that contain PDZ binding domains for the C terminus of intramembrane proteins. Cingulin, multi-PDZ protein 1 (MUPP1), and the membrane-associated guanylate kinase with an inverted orientation of protein-protmartes 15 de noviembre de 2011 interaction domain (MAGI) are examples of second-order adaptor molecules. The first- and second-order adaptor molecules together with signaling molecu
  63. 63. Barrera hematoencefálicamartes 15 de noviembre de 2011
  64. 64. Box 3 | Pathological states involving BBB breakdown or disorder permeability (little or no aquaporin)88–90, it is likely that the excess metabolic water joins the ISF being secreted Several pathologies of the CNS involve disturbance of blood–brain barrier (BBB) into the pericapillary space by the endothelium5. ISF out- function, and, in many of these, astrocyte–endothelial cooperation is also abnormal. flow involves perivascular spaces around large vessels, Stroke and clearance routes either through the CSF or following • Astrocytes secrete transforming growth factor-β (TGFβ), which downregulates brain alternative pathways to neck lymphatics. capillary endothelial expression of fibrinolytic enzyme tissue plasminogen activator Neurotransmitter recycling can also lead to local (tPA) and anticoagulant thrombomodulin (TM)150. changes in ions and water. Glutamate is the major excitatory transmitter of the brain, and astrocyte proc- Barrera hematoencefálica • Proteolysis of the vascular basement membrane/matrix151. • Induction of aquaporin 4 (AQP4) mRNA and protein at BBB disruption152. esses surrounding synapses can take up glutamate • Decrease in BBB permeability after treatment with arginine vasopressin V1 receptor through transport proteins (particularly EAAT1 and 2); antagonist in a stroke model153. the transport is Na+-dependent and accompanied by net uptake of ions and water, again contributing to Trauma water clearance at the BBB85. Glutamate is converted • Bradykinin, a mediator of inflammation, is produced and stimulates production and to glutamine within the astrocyte and recycled to the release of interleukin-6 (IL-6) from astrocytes, which leads to opening of the BBB102. neurons. The slight astrocytic cell swelling that accom- Infectious or inflammatory processes panies neuronal activity, resulting from activation by Examples include bacterial infections, meningitis, encephalitis and sepsis. glutamate or ion uptake, leads to several cellular mech- • The bacterial protein lipopolysaccharide affects the permeability of BBB tight anisms that contribute to the recovery of ionic balance junctions. This is mediated by the production of free radicals, IL-6 and IL-1β154. and cell volume, some of which involve elevated intra- • Interferon-β prevents BBB disruption155. cellular Ca2+ concentration66,91,92. Hence, there are many links between the signalling and regulatory processes Multiple sclerosis that occur in the neurovascular unit. • Breakdown of the BBB97. • Downregulation of laminin in the basement membrane156. BBB changes in pathology • Selective loss of claudin 1/3 in experimental autoimmune encephalomyelitis94. In a number of pathologies, the function of the BBB is altered (BOX 3), and several disorders appear to involve HIV disturbances of endothelial–glial interaction. Thus, • BBB tight junction disruption157,158. the capillaries of many glial tumours are more leaky Alzheimer’s disease than those of normal brain tissue, either as a result • Increased glucose transport, upregulation of glucose transporter GLUT1, altered of a lack of inductive factors, or owing to the release agrin levels, upregulation of AQP4 expression95,159. of permeability factors such as vascular endothelial • Accumulation of amyloid-β, a key neuropathological feature of Alzheimer’s disease, growth factor (VEGF). Moreover, the tight junction by decreased levels of P-glycoprotein transporter expression160. protein claudin 1/3 is downregulated in some brain tumours93,94. • Altered cellular relations at the BBB, and changes in the basal lamina and amyloid-β clearance100. In BBB disruption, agrin is lost from the abluminal surface of the brain endothelial cells adjacent to astro- Parkinson’s disease cytic endfeet11; this may contribute to BBB damage in • Dysfunction of the BBB by reduced efficacy of P-glycoprotein101. Alzheimer’s disease95, and to the redistribution of astro- Epilepsy cytic AQP4 in glioblastomas96. Astrocytic AQP4 expres- sion is upregulated in brain oedema triggered by BBB • Transient BBB opening in epileptogenic foci, and upregulated expression of breakdown. Such upregulation could be adaptive in P-glycoprotein and other drug efflux transporters in astrocytes and endothelium98,99. helping to clear the accumulating fluid, but the associ- Brain tumours ated cell swelling would tend to exacerbate the problem • Breakdown of the BBB161,162. under extreme conditions. Indeed, AQP4–/– mice show • Downregulation of tight junction protein claudin 1/3; redistribution of astrocyte protection against ischaemic brain oedema48. Some AQP4 and Kir4.1 (inwardly rectifying K+ channel)20,93,96. chronic neuropathologies such as multiple sclerosis may involve an early phase of BBB disturbance (involving Pain the downregulation of claudin 1/3 (REF. 11)) that precedes • Inflammatory pain alters BBB tight junction protein expression and BBB neuronal damage, which suggests that vascular damage permeability108. can lead to secondary neuronal disorder97. In epilepsy, the normal pattern of brain ABC trans- porter expression may change, with upregulation ofmartes 15 de noviembre de 2011 buffer) when neural activity ceases. Astrocytes can also Pgp on astrocytes and brain endothelium98,99; this may + + +
  65. 65. ronal groups in the regulation of neuroendocrine three families: sel functions. related receptors lar inflammation PMN and other developing infarc Barrera hematoencefálica the microvascula artery occlusion contribute to mic mation during t Adherence and through the po sequential intera sion molecule (I family consists o endothelial cells L-selectin (leuko and platelets me cytes and monoc sion molecules adhesion proper leukocyte transm the interaction endothelial cell I Fig. 14. Midline sagittal schematic drawing of the brain show- endothelial cell I ing circumventricular organs (dark shaded structures): NH, LFA-1). neurohypophysis; ME, median eminence; OVLT, organum vasculosum of lamina terminales; SFO, subfornicial organ; 4.3.2. CYTOKINE PI, pineal gland or body; SCO, subcommissural organ; AP, area postrema; CP, choroid plexus; OC, optic chiasm; AC, Ischemic cereb anterior commissure; CC, corpus callosum (lightly shaded oxide free radic areas). These are stimulamartes 15 de noviembre de 2011
  66. 66. Barrera hematoencefálicamartes 15 de noviembre de 2011
  67. 67. 1 junctions, bradykini leading to the releas Barrera hematoencefálica NF-κB B2 Bradykinin 3 amplify the effect by ET-1 Tumour necrosis fa TNFα Microglial cell permeability by dir and indirect effects lL-6 2 production and IL TNFα •O2– lL-1β LPS complex immunore Substance P can exacerbate CNS [Ca2+]i↑ 5-HT multiple sclerosis b Histamine activation of already ATP some mechanisms e PGs B2 Indeed, the ability of contribute to the lin tPA disease106. tPA It has recently be Capillary cytes and microglia Tight 4 pain107. As astrocyt junction TGFβ↓ connectivity and for gested that glia ma pain sensation. In in Endothelial from central and pe cell sue cells and blood Agrin? such as substance P K+ (CGRP), serotonin, AQP4 Glu BBB from both the b For example, the re Basal lamina Astrocyte 5 concentration or alt tion protein occludi Figure 6 | Astroglial–endothelial signalling under pathological conditions. TNFα, histamine an Examples of astroglial–endothelial signalling in infection or inflammation, stroke or matory pain can also trauma, leading to opening of the blood–brain barrier (BBB) and disturbance of brain permeability108.martes 15 de noviembre de 2011 function. bradykinin, produced during inflammation in stroke or brain trauma, acts on
  68. 68. 42 Endotelio cerebralmartes 15 de noviembre de 2011
  69. 69. 42 Endotelio cerebral Rico en mitocondriasmartes 15 de noviembre de 2011
  70. 70. 42 Endotelio cerebral Rico en mitocondrias Ausencia de pinocitosismartes 15 de noviembre de 2011
  71. 71. 42 Endotelio cerebral Rico en mitocondrias Ausencia de pinocitosis Ausencia de fenestracionesmartes 15 de noviembre de 2011
  72. 72. 42 Endotelio cerebral Rico en mitocondrias Ausencia de pinocitosis Ausencia de fenestracionesmartes 15 de noviembre de 2011
  73. 73. l. Encircling the basal lamina of 43or the pericyte are numerous pro- joined to one another by gap Endoteliod-Brain Barrier Refers to a cerebral of Physical, Metabolic, andoperties of the CapillaryEndotheliumbarrier is a complex anatomic orogic and osmotic barrier protect-ulating macromolecules, such asmin, do not cross the endothelial illaries. This contrasts with theulating macromolecules that nor- extracranial tissues. The originalblood-brain barrier is attributed1885, observed that intravenousblue, a dye that circulates bound the diffuse distribution of the dye n and tissue except the brain andblood-brain barrier describes theing macromolecules to enter the or interstitial fluid of the brainhe mechanical component of the Fig. 13. Normal rat brain capillary (original magnification ed primarily to structural charac- Â7000). The inset shows a close-up view of the capillary wall helial capillary lining of the brain to demonstrate a tight junction (arrows) (original magnifica-at are lacking in the endothelial tion Â32,200). martes 15 de noviembre de 2011
  74. 74. 44 Astrogliamartes 15 de noviembre de 2011
  75. 75. 44 Astroglia Inducción de la BHEmartes 15 de noviembre de 2011
  76. 76. 44 Astroglia Inducción de la BHE Mantenimiento de la BHEmartes 15 de noviembre de 2011
  77. 77. 44 Astroglia Inducción de la BHE Mantenimiento de la BHE Control del tono vascularmartes 15 de noviembre de 2011
  78. 78. 44 Astroglia Inducción de la BHE Mantenimiento de la BHE Control del tono vascular Estructura de la BHE?martes 15 de noviembre de 2011
  79. 79. 44 Astroglia Inducción de la BHE Mantenimiento de la BHE Control del tono vascular Estructura de la BHE?martes 15 de noviembre de 2011
  80. 80. 45 Pericitosmartes 15 de noviembre de 2011
  81. 81. 45 Pericitosmartes 15 de noviembre de 2011
  82. 82. 45 Pericitos Identidad oscura Células pluripotenciales Participación en inducción y maduración de la BHEmartes 15 de noviembre de 2011
  83. 83. LETTER 46 doi:10.1038/nature09522 Pericytes regulate the blood–brain barrier Annika Armulik1, Guillem Genove1, Maarja Mae1, Maya H. Nisancioglu1, Elisabet Wallgard1{, Colin Niaudet1, Liqun He1{, ´ ¨ Jenny Norlin1, Per Lindblom2, Karin Strittmatter1{, Bengt R. Johansson3 & Christer Betsholtz1 The blood–brain barrier (BBB) consists of specific physical barriers, (Fig. 1g, h, j and Supplementary Fig. 5a–c). Similarly, the fluorescent enzymes and transporters, which together maintain the necessary dye cadaverine Alexa Fluor-555 accumulated significantly in the brain extracellular environment of the central nervous system (CNS)1. parenchyma of Pdgfbret/ret and R26P1/0 mice (Fig. 1j and Supplemen- The main physical barrier is found in the CNS endothelial cell, tary Fig. 5d, h, i). Additionally, fluorescently labelled albumin, 70 kDa and depends on continuous complexes of tight junctions combined dextran and IgG passed the BBB in Pdgfbret/ret and R26P1/0 mice, but not with reduced vesicular transport2. Other possible constituents of the in controls or in R26P1/1 mice (Fig. 1j and Supplementary Fig. 5e–g). BBB include extracellular matrix, astrocytes and pericytes3, but the These experiments establish a close correlation between pericyte density relative contribution of these different components to the BBB and permeability across the BBB for a range of tracers of different remains largely unknown1,3. Here we demonstrate a direct role of molecular masses (Supplementary Table 1). pericytes at the BBB in vivo. Using a set of adult viable pericyte- Permeability in CNS vessels is impeded by continuous complexes of deficient mouse mutants we show that pericyte deficiency increases endothelial junctions13,14. We studied such complexes in adult pericyte- the permeability of the BBB to water and a range of low-molecular- deficient mutants using markers for adherens (VE-cadherin) and tight mass and high-molecular-mass tracers. The increased permeability (ZO-1 and claudin 5) junctions. Pdgfbret/ret, R26P1/0 and controls occurs by endothelial transcytosis, a process that is rapidly arrested showed junctional marker expression at similar levels as judged by by the drug imatinib. Furthermore, we show that pericytes function immunostaining and western blotting (Supplementary Fig. 6a–c and at the BBB in at least two ways: by regulating BBB-specific gene data not shown). The junctional markers were distributed in a pattern expression patterns in endothelial cells, and by inducing polariza- consistent with continuous junction complexes in both mutants and tion of astrocyte end-feet surrounding CNS blood vessels. Our controls; however, mutants displayed focally increased junctional width results indicate a novel and critical role for pericytes in the integ- and undulation. These patterns were confirmed by transmission elec- ration of endothelial and astrocyte functions at the neurovascular tron microscopy, which failed to reveal any apparent abnormalities in unit, and in the regulation of the BBB. the ultrastructure of endothelial junctions, with the exception that Platelet-derived growth factor (PDGF)-B/PDGF receptor-b (PDGFR- longer and irregular stretches of endothelial overlap were commonly b) signalling is necessary for pericyte recruitment during angiogenesis4,5. found in pericyte-deficient mutants (Fig. 2c and Supplementary Fig. 6e). Perinatal lethality precludes analysis of postnatal processes in Pdgfb or Because continuity, ultrastructure and marker expression were con- Pdgfrb null mice6,7, but several other mouse mutants of this pathway are sistent with retained integrity of endothelial junctions in the absence of viable postnatally. Two such mutants were used here: PDGF-B retention pericytes, we took advantage of the fixable nature of the fluorescent motif knockouts (Pdgfbret/ret) where PDGF-B binding to heparan sul- tracers to explore the route of extravasation in Pdgfbret/ret and R26P1/0 phate proteoglycans was disrupted8; and mutants in which Pdgfb null mice in more detail. Cadaverine Alexa Fluor-555 accumulated inmartes 15 de complemented by one or two copies of a conditionally silent alleles were noviembre de 2011 endothelial cells and in the brain parenchyma in Pdgfbret/ret and
  84. 84. LETTER 46 doi:10.1038/nature09522 Pericytes regulate the blood–brain barrier Annika Armulik1, Guillem Genove1, Maarja Mae1, Maya H. Nisancioglu1, Elisabet Wallgard1{, Colin Niaudet1, Liqun He1{, ´ ¨ Jenny Norlin1, Per Lindblom2, Karin Strittmatter1{, Bengt R. Johansson3 & Christer Betsholtz1 The blood–brain barrier (BBB) consists of specific physical barriers, (Fig. 1g, h, j and Supplementary Fig. 5a–c). Similarly, the fluorescent enzymes and transporters, which together maintain the necessary dye cadaverine Alexa Fluor-555 accumulated significantly in the brain extracellular environment of the central nervous system (CNS)1. parenchyma of Pdgfbret/ret and R26P1/0 mice (Fig. 1j and Supplemen- The main physical barrier is found in the CNS endothelial cell, tary Fig. 5d, h, i). Additionally, fluorescently labelled albumin, 70 kDa and depends on continuous complexes of tight junctions combined dextran and IgG passed the BBB in Pdgfbret/ret and R26P1/0 mice, but not Su deficit incrementa permeabilidad agua y otras moléculas with reduced vesicular transport2. Other possible constituents of the BBB include extracellular matrix, astrocytes and pericytes3, but the in controls or in R26P1/1 mice (Fig. 1j and Supplementary Fig. 5e–g). These experiments establish a close correlation between pericyte density mediante transcitosis relative contribution of these different components to the BBB remains largely unknown1,3. Here we demonstrate a direct role of and permeability across the BBB for a range of tracers of different molecular masses (Supplementary Table 1). pericytes at the BBB in vivo. Using a set of adult viable pericyte- Permeability in CNS vessels is impeded by continuous complexes of Regula la expresión génica de genes endoteliales de BHE deficient mouse mutants we show that pericyte deficiency increases the permeability of the BBB to water and a range of low-molecular- endothelial junctions13,14. We studied such complexes in adult pericyte- deficient mutants using markers for adherens (VE-cadherin) and tight mass and high-molecular-mass tracers. The increased permeability (ZO-1 and claudin 5) junctions. Pdgfbret/ret, R26P1/0 and controls Induce polarización de pies astrocitarios occurs by endothelial transcytosis, a process that is rapidly arrested showed junctional marker expression at similar levels as judged by by the drug imatinib. Furthermore, we show that pericytes function immunostaining and western blotting (Supplementary Fig. 6a–c and at the BBB in at least two ways: by regulating BBB-specific gene data not shown). The junctional markers were distributed in a pattern expression patterns in endothelial cells, and by inducing polariza- consistent with continuous junction complexes in both mutants and Participación en inducción y maduración de la BHE tion of astrocyte end-feet surrounding CNS blood vessels. Our results indicate a novel and critical role for pericytes in the integ- controls; however, mutants displayed focally increased junctional width and undulation. These patterns were confirmed by transmission elec- regulando la relación astrocito-endotelio ration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the BBB. tron microscopy, which failed to reveal any apparent abnormalities in the ultrastructure of endothelial junctions, with the exception that Platelet-derived growth factor (PDGF)-B/PDGF receptor-b (PDGFR- longer and irregular stretches of endothelial overlap were commonly b) signalling is necessary for pericyte recruitment during angiogenesis4,5. found in pericyte-deficient mutants (Fig. 2c and Supplementary Fig. 6e). Perinatal lethality precludes analysis of postnatal processes in Pdgfb or Because continuity, ultrastructure and marker expression were con- Pdgfrb null mice6,7, but several other mouse mutants of this pathway are sistent with retained integrity of endothelial junctions in the absence of viable postnatally. Two such mutants were used here: PDGF-B retention pericytes, we took advantage of the fixable nature of the fluorescent motif knockouts (Pdgfbret/ret) where PDGF-B binding to heparan sul- tracers to explore the route of extravasation in Pdgfbret/ret and R26P1/0 phate proteoglycans was disrupted8; and mutants in which Pdgfb null mice in more detail. Cadaverine Alexa Fluor-555 accumulated inmartes 15 de complemented by one or two copies of a conditionally silent alleles were noviembre de 2011 endothelial cells and in the brain parenchyma in Pdgfbret/ret and
  85. 85. martes 15 de noviembre de 2011
  86. 86. Perycitemartes 15 de noviembre de 2011
  87. 87. Perycitemartes 15 de noviembre de 2011
  88. 88. Uniones densas (TJ)martes 15 de noviembre de 2011
  89. 89. Uniones densas (TJ)martes 15 de noviembre de 2011
  90. 90. martes 15 de noviembre de 2011
  91. 91. Apical membrane Cingulin, JACOP, PAR3/6, CASK, 7H6, Itch, MUPP1, Claudin 3, 5, 12 MAGI-1–3, ZONAB ZO-2 Occludin AF6, RGS5 Tight junction JAMs, ZO-3 ESAM ZO-1 Basolateral membrane PECAM α-, β-, γ-Catenin, Desmoplakin, Adherens p120ctn, ZO-1 junction Actin/vinculin-based VE-cadherin cytoskeleton Basal laminaFigure 4 | Molecular composition of endothelial tight junctions. Simplified andincomplete scheme showing the molecular composition of endothelial tightmartes 15 de noviembre de 2011
  92. 92. Uniones densas (TJ)martes 15 de noviembre de 2011
  93. 93. Uniones densas (TJ)martes 15 de noviembre de 2011
  94. 94. Barrera hematoencefálicamartes 15 de noviembre de 2011
  95. 95. Barrera hematoencefálicamartes 15 de noviembre de 2011
  96. 96. Barrera hematoencefálicamartes 15 de noviembre de 2011
  97. 97. Barrera hematoencefálicamartes 15 de noviembre de 2011
  98. 98. 54 Actinamartes 15 de noviembre de 2011
  99. 99. 54 Actinamartes 15 de noviembre de 2011
  100. 100. 55 Barrera hematoencefálica Célulasmartes 15 de noviembre de 2011
  101. 101. 55 Barrera hematoencefálicaS REVIEW Basal lamina Neuron Interneuron Tight junction AstrocyteTight junction Células Pericyte CapillaryA belt-like region of adhesion Astrocyte Endothelialbetween adjacent cells. Tight celljunctions regulate paracellularflux, and contribute to the b LIFmaintenance of cell polarity bystopping molecules from a Tightdiffusing within the plane of the TGFβ junctionmembrane. Tight ? bFGF GLUT1Abluminal membrane junction CapillaryThe endothelial cell membrane ANG1that faces away from the vessel Capillary Endotheliallumen, towards the brain. Microglia LAT1 cellMeninges Endothelial Pgp GDNF cellThe complex arrangement of EAAT1–3 Astrocytethree protective membranessurrounding the brain, with a Basalthick outer connective tissue laminalayer (dura) overlying the ET1 TIE2 P2Y2 5-HTbarrier layer (arachnoid), and Figure 2 | Cellular constituents of the blood–brain barrier. The barrier is formed by capillary endothelial cells,finally the thin layer coveringthe glia limitans (pia). The sub- surrounded by basal lamina and astrocytic perivascular endfeet. Astrocytes provide the cellular link to the neurons.arachnoid layer has a sponge- The figure also shows pericytes and microglial cells. a | Brain endothelial cell features observed in cell culture. Thelike structure filled with CSF.martes 15 de noviembre cells express a number of transporters and receptors, some of which are shown. EAAT1–3, excitatory amino acid de 2011
  102. 102. 56 Regulación de la permeabilidad vascularmartes 15 de noviembre de 2011
  103. 103. 56 Regulación de la permeabilidad vascularmartes 15 de noviembre de 2011
  104. 104. 57 Unidad neurogliovasculareuronReviewure 4. Schematic of the Neurovascular UnitEndothelial cells and pericytes are separated by the basement membrane. Pericyte processes sheathe most of the outer side of the basement membrnts of contact, pericytes communicate directly with endothelial cells through the synapse-like peg-socket contacts. Astrocytic endfoot processes uns microvessel wall, which is made up of endothelial cells and pericytes. Resting microglia have a ‘‘ramified’’ shape. In cases of neuronal disorders thimary vascular origin, circulating neurotoxins may cross the BBB to reach their neuronal targets, or proinflammatory signals from the vascular cells or r illary blood flow may disrupt normal synaptic transmission and trigger neuronal injury (arrow 1). Microglia recruited from the blood or within the brain martes 15 de noviembre de 2011
  105. 105. 58 Red capilarmartes 15 de noviembre de 2011
  106. 106. 58 Red capilarmartes 15 de noviembre de 2011
  107. 107. Desarrollo vascular Extracraneal Intracraneal Troncos perpendiculares Arborizaciónmartes 15 de noviembre de 2011
  108. 108. martes 15 de noviembre de 2011
  109. 109. Desarrollo vascularmartes 15 de noviembre de 2011
  110. 110. Desarrollo vascularmartes 15 de noviembre de 2011
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  113. 113. Texto 63 Carmeliet and Tessier-Lavigne, Nature. 2005martes 15 de noviembre de 2011
  114. 114. Neuron. 2011. 71(3)Quaegebeur A, Lange C, Carmeliet P. 64martes 15 de noviembre de 2011
  115. 115. martes 15 de noviembre de 2011
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  119. 119. 0 dpn 69martes 15 de noviembre de 2011
  120. 120. 7 dpn 70martes 15 de noviembre de 2011
  121. 121. 14 dpn 71martes 15 de noviembre de 2011
  122. 122. 21 dpn 72martes 15 de noviembre de 2011
  123. 123. 60 dpn 73martes 15 de noviembre de 2011
  124. 124. martes 15 de noviembre de 2011
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