Vascularización Cerebral

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Vascularización Cerebral

  1. 1. Vascularización cerebral Laboratorio de Neurociencia Clínica y Experimental (LaNCE) Euskal Herriko Unibertsitatea http://www.ehu.es/ehusfera/lance sábado 29 de mayo de 2010
  2. 2. Vascularización cerebral Enrike G. Argandoña Laboratorio de Neurociencia Clínica y Experimental (LaNCE) Euskal Herriko Unibertsitatea http://www.ehu.es/ehusfera/lance sábado 29 de mayo de 2010
  3. 3. LaNCE sábado 29 de mayo de 2010
  4. 4. José Vicente Lafuente, Enrike G. Argandoña, Harkaitz Bengoetxea, Susana Bulnes, Naiara Ortuzar, Álvaro García-Blanco, Irantzu Rico-Barrio, Itsasne Bustillo sábado 29 de mayo de 2010
  5. 5. Vascularización cerebral 4 sábado 29 de mayo de 2010
  6. 6. Vascularización cerebral Sistema arterial aferente 4 sábado 29 de mayo de 2010
  7. 7. Vascularización cerebral Sistema arterial aferente Sistema venoso eferente 4 sábado 29 de mayo de 2010
  8. 8. Vascularización cerebral 5 sábado 29 de mayo de 2010
  9. 9. Vascularización cerebral 1% volumen cerebral 5 sábado 29 de mayo de 2010
  10. 10. Vascularización cerebral 1% volumen cerebral 20% Gasto cardiaco 5 sábado 29 de mayo de 2010
  11. 11. Vascularización cerebral 1% volumen cerebral 20% Gasto cardiaco 65% consumo energía 5 sábado 29 de mayo de 2010
  12. 12. sábado 29 de mayo de 2010
  13. 13. sábado 29 de mayo de 2010
  14. 14. Vascularización cerebral 7 sábado 29 de mayo de 2010
  15. 15. Vascularización cerebral Control de la circulación sistémica 7 sábado 29 de mayo de 2010
  16. 16. Vascularización cerebral Control de la circulación sistémica Autorregulación vascularización cerebral 7 sábado 29 de mayo de 2010
  17. 17. Vascularización cerebral Control de la circulación sistémica Autorregulación vascularización cerebral Distribución del flujo 7 sábado 29 de mayo de 2010
  18. 18. 8 Vascularización cerebral sábado 29 de mayo de 2010
  19. 19. 8 Vascularización cerebral sábado 29 de mayo de 2010
  20. 20. sábado 29 de mayo de 2010
  21. 21. sábado 29 de mayo de 2010
  22. 22. sábado 29 de mayo de 2010
  23. 23. sábado 29 de mayo de 2010
  24. 24. 11 sábado 29 de mayo de 2010
  25. 25. 11 sábado 29 de mayo de 2010
  26. 26. 11 sábado 29 de mayo de 2010
  27. 27. 11 sábado 29 de mayo de 2010
  28. 28. Vascularización intracerebral 12 sábado 29 de mayo de 2010
  29. 29. Vascularización intracerebral Arteriolas (50-100 µm) 12 sábado 29 de mayo de 2010
  30. 30. Vascularización intracerebral Arteriolas (50-100 µm) Arteriolas terminales (10-100µm) 12 sábado 29 de mayo de 2010
  31. 31. Vascularización intracerebral Arteriolas (50-100 µm) Arteriolas terminales (10-100µm) Vénulas (± 30 µm) 12 sábado 29 de mayo de 2010
  32. 32. Vascularización intracerebral Arteriolas (50-100 µm) Arteriolas terminales (10-100µm) Vénulas (± 30 µm) Capilares (<30 µm) 12 sábado 29 de mayo de 2010
  33. 33. Vascularización cortical Red capilar 640 km (reducida en Alzheimer) Un capilar por neurona Barrera hematoencefálica Mecanismos estructurales Mecanismos metabólicos sábado 29 de mayo de 2010
  34. 34. Barreras cerebrales sábado 29 de mayo de 2010
  35. 35. Barreras cerebrales sábado 29 de mayo de 2010
  36. 36. 15 Barrera hematoencefálica sábado 29 de mayo de 2010
  37. 37. 15 Barrera hematoencefálica sábado 29 de mayo de 2010
  38. 38. 15 Barrera hematoencefálica sábado 29 de mayo de 2010
  39. 39. 16 Barrera hematoencefálica sábado 29 de mayo de 2010
  40. 40. 16 Barrera hematoencefálica sábado 29 de mayo de 2010
  41. 41. Tipos de transporte sábado 29 de mayo de 2010
  42. 42. 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 –+ + + – + + –+ + + – – – 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-soluble sábado 29 de mayo de 2010
  43. 43. sábado 29 de mayo de 2010
  44. 44. 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 Neuron Figure 5 | Complex cell–cell signalling at the blood–brain barrier. A portion of a brain capillary wall, showing the main cell types present with the potential to signal to each other. Pericytes are enclosed within the endothelial basal lamina and form the closest associations with endothelium. The endfeet of astrocytic glial cells are apposed sábado 29 de mayo de 2010
  45. 45. 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-prot sábado 29 de mayo de 2010 interaction domain (MAGI) are examples of second-order adaptor molecules. The first- and second-order adaptor molecules together with signaling molecu
  46. 46. Barrera hematoencefálica sábado 29 de mayo de 2010
  47. 47. 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 of sábado 29 de mayo de 2010 buffer) when neural activity ceases. Astrocytes can also Pgp on astrocytes and brain endothelium98,99; this may + + +
  48. 48. 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 stimula sábado 29 de mayo de 2010
  49. 49. Barrera hematoencefálica sábado 29 de mayo de 2010
  50. 50. 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. sábado 29 de mayo de 2010 function. bradykinin, produced during inflammation in stroke or brain trauma, acts on
  51. 51. 23 Endotelio cerebral sábado 29 de mayo de 2010
  52. 52. 23 Endotelio cerebral Rico en mitocondrias sábado 29 de mayo de 2010
  53. 53. 23 Endotelio cerebral Rico en mitocondrias Ausencia de pinocitosis sábado 29 de mayo de 2010
  54. 54. 23 Endotelio cerebral Rico en mitocondrias Ausencia de pinocitosis Ausencia de fenestraciones sábado 29 de mayo de 2010
  55. 55. 23 Endotelio cerebral Rico en mitocondrias Ausencia de pinocitosis Ausencia de fenestraciones sábado 29 de mayo de 2010
  56. 56. l. Encircling the basal lamina of 24 or the pericyte are numerous pro- joined to one another by gap Endotelio d-Brain Barrier Refers to a cerebral of Physical, Metabolic, and operties of the Capillary Endothelium barrier is a complex anatomic or ogic and osmotic barrier protect- ulating macromolecules, such as min, do not cross the endothelial illaries. This contrasts with the ulating macromolecules that nor- extracranial tissues. The original blood-brain barrier is attributed 1885, observed that intravenous blue, a dye that circulates bound the diffuse distribution of the dye n and tissue except the brain and blood-brain barrier describes the ing macromolecules to enter the or interstitial fluid of the brain he 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). sábado 29 de mayo de 2010
  57. 57. 25 Astroglia sábado 29 de mayo de 2010
  58. 58. 25 Astroglia Inducción de la BHE sábado 29 de mayo de 2010
  59. 59. 25 Astroglia Inducción de la BHE Mantenimiento de la BHE sábado 29 de mayo de 2010
  60. 60. 25 Astroglia Inducción de la BHE Mantenimiento de la BHE Control del tono vascular sábado 29 de mayo de 2010
  61. 61. 25 Astroglia Inducción de la BHE Mantenimiento de la BHE Control del tono vascular Estructura de la BHE? sábado 29 de mayo de 2010
  62. 62. 25 Astroglia Inducción de la BHE Mantenimiento de la BHE Control del tono vascular Estructura de la BHE? sábado 29 de mayo de 2010
  63. 63. 26 Pericitos sábado 29 de mayo de 2010
  64. 64. 26 Pericitos sábado 29 de mayo de 2010
  65. 65. 26 Pericitos Identidad oscura Células pluripotenciales Participación en inducción y maduración de la BHE sábado 29 de mayo de 2010
  66. 66. Uniones densas (TJ) sábado 29 de mayo de 2010
  67. 67. Uniones densas (TJ) sábado 29 de mayo de 2010
  68. 68. sábado 29 de mayo de 2010
  69. 69. 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 lamina Figure 4 | Molecular composition of endothelial tight junctions. Simplified and incomplete scheme showing the molecular composition of endothelial tight sábado 29 de mayo de 2010
  70. 70. Uniones densas (TJ) sábado 29 de mayo de 2010
  71. 71. Uniones densas (TJ) sábado 29 de mayo de 2010
  72. 72. Barrera hematoencefálica sábado 29 de mayo de 2010
  73. 73. Barrera hematoencefálica sábado 29 de mayo de 2010
  74. 74. Barrera hematoencefálica sábado 29 de mayo de 2010
  75. 75. Barrera hematoencefálica sábado 29 de mayo de 2010
  76. 76. 31 Actina sábado 29 de mayo de 2010
  77. 77. 31 Actina sábado 29 de mayo de 2010
  78. 78. 32 Barrera hematoencefálica Células sábado 29 de mayo de 2010
  79. 79. 32 Barrera hematoencefálicaS REVIEW Basal lamina Neuron Interneuron Tight junction Astrocyte Tight junction Células Pericyte Capillary A belt-like region of adhesion Astrocyte Endothelial between adjacent cells. Tight cell junctions regulate paracellular flux, and contribute to the b LIF maintenance of cell polarity by stopping molecules from a Tight diffusing within the plane of the TGFβ junction membrane. Tight ? bFGF GLUT1 Abluminal membrane junction Capillary The endothelial cell membrane ANG1 that faces away from the vessel Capillary Endothelial lumen, towards the brain. Microglia LAT1 cell Meninges Endothelial Pgp GDNF cell The complex arrangement of EAAT1–3 Astrocyte three protective membranes surrounding the brain, with a Basal thick outer connective tissue lamina layer (dura) overlying the ET1 TIE2 P2Y2 5-HT barrier layer (arachnoid), and Figure 2 | Cellular constituents of the blood–brain barrier. The barrier is formed by capillary endothelial cells, finally the thin layer covering the 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. The like structure filled with CSF. sábado 29 de mayo de 2010 express a number of transporters and receptors, some of which are shown. EAAT1–3, excitatory amino acid cells
  80. 80. 33 Regulación de la permeabilidad vascular sábado 29 de mayo de 2010
  81. 81. 33 Regulación de la permeabilidad vascular sábado 29 de mayo de 2010
  82. 82. 34 Unidad neurogliovascular euron Review ure 4. Schematic of the Neurovascular Unit Endothelial cells and pericytes are separated by the basement membrane. Pericyte processes sheathe most of the outer side of the basement membr nts 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 th imary 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 sábado 29 de mayo de 2010 sel wall can sense signals from neurons (arrow 2). Activated endothelium, microglia, and astrocytes signal back to neurons, which in most cases agg
  83. 83. 35 Red capilar sábado 29 de mayo de 2010
  84. 84. 35 Red capilar sábado 29 de mayo de 2010
  85. 85. Desarrollo vascular Extracraneal Intracraneal Troncos perpendiculares Arborización sábado 29 de mayo de 2010
  86. 86. sábado 29 de mayo de 2010
  87. 87. Desarrollo vascular sábado 29 de mayo de 2010
  88. 88. Desarrollo vascular sábado 29 de mayo de 2010
  89. 89. sábado 29 de mayo de 2010
  90. 90. sábado 29 de mayo de 2010
  91. 91. 0 dpn 40 sábado 29 de mayo de 2010
  92. 92. 7 dpn 41 sábado 29 de mayo de 2010
  93. 93. 14 dpn 42 sábado 29 de mayo de 2010
  94. 94. 21 dpn 43 sábado 29 de mayo de 2010
  95. 95. 60 dpn 44 sábado 29 de mayo de 2010
  96. 96. sábado 29 de mayo de 2010
  97. 97. VEGF Vascular Endothelial Growth Factor I. Inductor de: • Proliferación endotelial • Migración endotelial • Inhibición apotosis II. Efectos neurotróficos y neuroprotectores III. Permeabilidad vascular sábado 29 de mayo de 2010
  98. 98. VEGF Vascular Endothelial Growth Factor sábado 29 de mayo de 2010
  99. 99. VEGF en angiogénesis 48 sábado 29 de mayo de 2010
  100. 100. VEGF en angiogénesis 48 sábado 29 de mayo de 2010
  101. 101. VEGF en angiogenesis sábado 29 de mayo de 2010
  102. 102. Neuroproteccion VEGF en sábado 29 de mayo de 2010
  103. 103. VEGF Efectos neurotróficos sábado 29 de mayo de 2010
  104. 104. VEGF Hiperpermeabilidad ZO-1 VEGF Actina sábado 29 de mayo de 2010
  105. 105. Angiogénesis sábado 29 de mayo de 2010
  106. 106. Angiogénesis sábado 29 de mayo de 2010
  107. 107. Angiogénesis sábado 29 de mayo de 2010
  108. 108. Angiogénesis sábado 29 de mayo de 2010
  109. 109. Angiogénesis sábado 29 de mayo de 2010
  110. 110. Angiogénesis sábado 29 de mayo de 2010
  111. 111. Mechanism of BOLD Functional MRI Brain activity Oxygen consumption Cerebral blood flow Oxyhemoglobin Deoxyhemoglobin Magnetic susceptibility T2* MRI signal intesity sábado 29 de mayo de 2010
  112. 112. Oxyhemoglobin and Deoxyhemoglobin in Veins during Brain Activation Rest Activation Normal blood flow High blood flow Oxyhemoglobin Deoxyhemoglobin sábado 29 de mayo de 2010
  113. 113. Signal Intensity Time Series and Activation Maps Off On Off On Off On Off On Scan Number sábado 29 de mayo de 2010
  114. 114. Multi-Slice Spiral Images sábado 29 de mayo de 2010
  115. 115. Multi-Slice EPI Images sábado 29 de mayo de 2010
  116. 116. Activation Maps on Anatomical Images MS Spiral MS EPI 3D Spiral sábado 29 de mayo de 2010
  117. 117. Visual Activation Maps (ISI=12s) sábado 29 de mayo de 2010
  118. 118. sábado 29 de mayo de 2010 All images courtesy of Johann Wolfgang G oethe University Hospital,
  119. 119. BOLD MRI MAPP BrainLA B is the o of B O LD MRI func imaging (DTI) for u integration of both tion not only abou white matter struc The result is a com completely new in ning that sets the MORE COMPRE MRI DATA West Virginia Universi A. Puce, PhD, Profess Center for Advanced I W. Boling, MD, Neuros M. Parson, PhD, Depa Functional MRI pl cedures in or nea imaging based on sábado 29 de mayo de 2010 structures involve
  120. 120. Angiogénesis y neurogénesis Dos caminos paralelos sábado 29 de mayo de 2010
  121. 121. Desarrollo cortical Predeterminado genéticamente Mediado por experiencia sábado 29 de mayo de 2010
  122. 122. Desarrollo cortical Predeterminado genéticamente Mediado por experiencia PERIODO CRÍTICO 3ª - 5ª semanas sábado 29 de mayo de 2010
  123. 123. Neurogenesis Angiogenesis ? sábado 29 de mayo de 2010
  124. 124. Neurogenesis Angiogenesis ? sábado 29 de mayo de 2010
  125. 125. Neurogenesis Angiogenesis ? sábado 29 de mayo de 2010
  126. 126. Neurogenesis Angiogenesis Nicho vascular (neurogenesis). Palmer 2000. Incremento demanda. Black 1987. Coordinados. Carmeliet 2005. sábado 29 de mayo de 2010
  127. 127. Desarrollo neurovascular Evento coordinado Respuesta común a señales comunes VEGF Neurotrofinas (NGF, BDNF, NTs) Neuropilinas (Nrp1, Nrp2) Semaforinas (Sema3A) Efrinas/Ephs (EphB-ephrinB) Angiopoyetinas (Ang2) sábado 29 de mayo de 2010
  128. 128. Sistema visual Sistema Visual sábado 29 de mayo de 2010
  129. 129. Periodo crítico 4ª semana Cambios mediados por experiencia 1º-3ª semanas 4ª-6ª semanas 7ª y 8ª semanas Periodo precritico Periodo crítico Periodo postcrítico Age sábado 29 de mayo de 2010
  130. 130. Empobrecimiento ambiental Descenso densidades neuronal, glial y vascular Retraso maduración Anulación cierre periodo crítico sábado 29 de mayo de 2010
  131. 131. Empobrecimiento ambiental sábado 29 de mayo de 2010
  132. 132. Cortical parameters sábado 29 de mayo de 2010
  133. 133. Cortical parameters sábado 29 de mayo de 2010
  134. 134. Cortical parameters sábado 29 de mayo de 2010
  135. 135. Vascular density sábado 29 de mayo de 2010
  136. 136. Vascular density sábado 29 de mayo de 2010
  137. 137. Results 120 25 100 20 80 15 Oscuridad 60 Controles 10 40 5 20 0 0 0 DPN 7 DPN 14 DPN 21 DPN 60 DPN 0 DPN 7 DPN 14 DPN 21 DPN 60 DPN Number of Vascular Density perpendicular vessels sábado 29 de mayo de 2010
  138. 138. Enriquecimiento ambiental Donald Hebb (1949) Kresh, Bennett, Rosenzweig, Diamond (60s) Combinación de complejidad de objetos inanimados y estimulación social. sábado 29 de mayo de 2010
  139. 139. Enriquecimiento ambiental Cambios anatómicos Plasticidad neuronal Sinaptogénesis Morfología sináptica Neurogénesis Neurotrofinas (BDNF, NGF, NT-3,VEGF) Gliogénesis sábado 29 de mayo de 2010
  140. 140. Enriquecimiento ambiental Reduce el deficit de memoria tras ictus (Dahlqvist, 2004) Mejora la recuperiación funcional tras lesión estriatal (Dobrossy 2004) Induce neurogenesis en hipocampo (Kempermann 1997) Reduce los efectos del Hungtington (Spires 2004) Madura y consolida la corteza visual en ratas privadas de luz (Bertoletti 2004) Revierte los efectos del stress prenatal (Morley-Fletcher 2003) Acelera el desarrollo de la corteza visual (Cancedda 2004) sábado 29 de mayo de 2010
  141. 141. Enriquecimiento ambiental sábado 29 de mayo de 2010
  142. 142. Enriquecimiento ambiental sábado 29 de mayo de 2010
  143. 143. Enriquecimiento ambiental sábado 29 de mayo de 2010
  144. 144. Enriquecimiento ambiental Edades : . 14 dpn, 21 dpn Pre-critical . 28 dpn, 35 dpn, 42 dpn Critical period . 49 dpn, 56 dpn, 63 dpn Postcritical sábado 29 de mayo de 2010
  145. 145. sábado 29 de mayo de 2010
  146. 146. Estudio cualitativo sábado 29 de mayo de 2010 Inmunohistoquimia Histoquimia LEA EBA GluT-1
  147. 147. LEA EBA Estudio cualitativo sábado 29 de mayo de 2010
  148. 148. Estudio cualitativo EBA GluT-1 EBA + GluT-1 sábado 29 de mayo de 2010
  149. 149. Enriquecimiento ambiental Angiogénesis sábado 29 de mayo de 2010
  150. 150. Estudio cuantitativo sábado 29 de mayo de 2010
  151. 151. VEGF WESTERN BLOT ELISA sábado 29 de mayo de 2010
  152. 152. sábado 29 de mayo de 2010
  153. 153. ELISA sábado 29 de mayo de 2010
  154. 154. VEGF levels 6,0 CE Control DR DR-CE 4,5 3,0 1,5 0 14 dpn 21 dpn 28 dpn 35 dpn 42 dpn 49 dpn 56 dpn 63 dpn sábado 29 de mayo de 2010
  155. 155. sábado 29 de mayo de 2010
  156. 156. [Cell Adhesion & Migration 3:2, 199-204; April/May/June 2009]; ©2009 Landes Bioscience Special Focus: Angiogenesis in the Central Nervous System Neurovascular development The beginning of a beautiful friendship Victoria L. Bautch1,2,* and Jennifer M. James1 1Department of Biology; 2Carolina Cardiovascular Biology Center; The University of North Carolina at Chapel Hill; Chapel Hill, NC USA Key words: neural development, vascular development, neural tube, spinal cord, central nervous system, peri-neural vascular plexus, vessel sprouting, angiogenesis, neural stem cell, vascular niche sábado 29 de mayo de 2010
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  158. 158. !! )! ! )!!#!# !"#$%&'"!"#$$%& '()*!+$,++++-.,+/0%1234$,#$$%,$++$5,6 !"#$%&'()*+*,&%$*)%$),*-.%,*/)01,)*23%,124*25'() Blackwell Publishing Ltd *2,%&"4*25)51)100$*5)5"*)-.'25%5'5%3*)*00*&5$)10) β /',67,*',%28)12)5"*)97:;;β)'$5,1&#5%&)/*2$%5#)%2)5"*) ,'5)3%$.'()&1,5*+ MA>)N:!J,!;>OBA'(PBQ+Q#QR!SB>NB)=T!K:AO(:=6:B#QR!BA'!@(?U!V,!WBI<:A=:#QR + ()*&+',)%'#-.#/0+12%3#4#&%5##6&7-+&'-+8#-.#9:2%2;&:#&%5#<=*)+2,)%'&:#/)0+-1;2)%;)#>6&/9<?@#()*&+',)%'#-.#/)0+-1;2)%;)@# A&;0:'8#-.#B)52;2%)#&%5#C5-%'-:-38@#D&1E0)#9-0%'+8#F%2G)+12'8@#D&++2-#H&++2)%&@#IJKIL#6)2-&@#H*&2% <=$5,'&5 ;I=:>!X)>=9Q!:6F(?<>:!=(!Y)?<BC!)AF<=?!E('<CB=:?!D(>=)DBC!':Y:C(FE:A=Q!)A'<D)AO!A<E:>(<?!D9BAO:?!)A!BCC!(I!=9: D(EF(A:A=?!(I!=9:!Y)?<BC!D(>=:6,!Z(?=!(I!=9:!D(>=)DBC!D9BAO:?!=9<?!)A'<D:'!(DD<>!'<>)AO![9B=!)?!DBCC:'!=9:!D>)=)DBC F:>)(',!;?=>(DH=:?!FCBH!BA!)EF(>=BA=!>(C:!)A!=9:!':Y:C(FE:A=Q!EB)A=:ABAD:!BA'!FCB?=)D)=H!(I!=9:!D(>=:6!B?![:CC!B? )A!=9:!?=><D=<>:!BA'!I<AD=)(A!(I!=9:!YB?D<CB>!A:=[(>N,!V)?<BC!':F>)YB=)(A!)A'<D:?!B!':D>:B?:!)A!=9:!B?=>(OC)BC F(F<CB=)(AQ![9:>:B?!:A9BAD:'!:6F:>):AD:!)AD>:B?:?!)=,!M6F(?<>:!=(!BA!:A>)D9:'!:AY)>(AE:A=!9B?!X::A!?9([A =(!F>:Y:A=!=9:!:II:D=?!(I!'B>N1>:B>)AO!)A!=9:!Y)?<BC!D(>=:6,!<>!F<>F(?:![B?!=(!?=<'H!=9:!:II:D=?!(I!BA!:A>)D9:' :AY)>(AE:A=!(A!=9:!':A?)=H!(I!B?=>(DH=:?!F:>!>:I:>:AD:!?<>IBD:!B=!=9:!Y)?<BC!D(>=:6!(I!'B>N1>:B>:'!>B=?Q!)A!(>':>!=( ':=:>E)A:!)I!:A9BAD:'!:6F:>):AD:!)?!BXC:!=(!D(EF:A?B=:!=9:!]<BA=)=B=)Y:!:II:D=?!(I!Y)?<BC!':F>)YB=)(A!BA'!=9:!>(C: (I!F9H?)DBC!:6:>D)?:!(A!=9:!:A>)D9E:A=!FB>B')OE,!^>:OABA=!GF>BO<:1_B[C:H!>B=?![:>:!>B)?:'!)A!(A:!(I!=9:!I(CC([)AO >:B>)AO!D(A')=)(A?*!D(A=>(C!>B=?![)=9!?=BA'B>'!9(<?)AO!"+#19!C)O9=-'B>N!DHDC:&`!)A!=(=BC!'B>NA:??!I(>!=9:!'B>N1>:B>)AO :6F:>)E:A=?`! BA'! 'B>N1>:B>)AO! )A! D(A')=)(A?! (I! :A>)D9:'! :AY)>(AE:A=! [)=9(<=! BA'! [)=9! F9H?)DBC! :6:>D)?:,! 89: B?=>(DH=)D!':A?)=H![B?!:?=)EB=:'!XH!)EE<A(9)?=(D9:E)?=>H!I(>!G1+$$β!F>(=:)A,!a<BA=)I)DB=)(A?![:>:!F:>I(>E:'!)A CBH:>!LV,!89:!?(EB=(?:A?(>)BC!D(>=:6!XB>>:C!I):C'![B?!BC?(!?=<'):'!B?!D(A=>(C,!89:!Y(C<E:!(I!CBH:>!LV![B?!?=:>:(C(O)DBCCH DBCD<CB=:'!I(>!:BD9!>:O)(AQ!BO:!BA'!:6F:>)E:A=BC!D(A')=)(A,!b>(E!=9:!X:O)AA)AO!(I!=9:!D>)=)DBC!F:>)('Q!B?=>(DH=: ':A?)=H![B?!9)O9:>!)A!D(A=>(C!>B=?!=9BA!)A!=9:!:A>)D9:'!:AY)>(AE:A=!O>(<F![)=9(<=!F9H?)DBC!:6:>D)?:Q![)=9!':A?)=):? (I!B?=>(DH=:?!B>(<A'!#$c!9)O9:>!B=!BCC!(I!=9:!')II:>:A=!BO:?,!LA!D(A=>B?=Q![9:A!=9:!BA)EBC?!9B'!BDD:??!=(!Y(C<A=B>H :6:>D)?:Q!':A?)=):?![:>:!?)OA)I)DBA=CH!9)O9:>!=9BA!:Y:A!=9:!D(A=>(C!>B=?,!<>!EB)A!>:?<C=!?9([?!=9B=!?=>B=:O):?!=( BFFCH!:AY)>(AE:A=BC!:A>)D9E:A=!?9(<C'!BC[BH?!D(A?)':>!=9:!)AD(>F(>B=)(A!(I!F9H?)DBC!:6:>D)?:Q!:Y:A!I(>!?:A?(>)BC B>:B?!?<D9!B?!=9:!Y)?<BC!B>:BQ![9:>:!D(EFC:6!:A>)D9:'!:6F:>):AD:!XH!)=?:CI!)?!A(=!:A(<O9!=(!D(EF:A?B=:!=9:!:II:D=? (I!Y)?<BC!':F>)YB=)(A, >*#)?1,/$ B?=>(OC)B`!'B>N1>:B>)AO`!:AY)>(AE:A=BC!:A>)D9E:A=`!G1+$$β`!Y)?<BC!D(>=:6`![9::C!><AA)AO, Y)?<BC!D(>=:6!)?!X:=[::A!=9:!=9)>'!BA'!I)I=9!F(?=AB=BC![::N @25,1/.&5%12 [)=9!B!F:BN!B=!=9:!I(<>=9![::N!"bBO)(C)A)!:=!BC,!+%%/&,!G(E: 89:!F(?=AB=BC!':Y:C(FE:A=!(I!=9:!Y)?<BC!D(>=:6!)?!E('<1 B<=9(>?! 9BY:! ?=<'):'! =9:! :II:D=?! (I! =9:! )AD>:B?:! BA'-(> CB=:'!XH!:6F:>):AD:Q![9)D9!?9BF:?!I<AD=)(ABC!BA'!D(>=)DBC ':F>)YB=)(A!(I!Y)?<BC!:6F:>):AD:!(A!=9:!A:<>(ABC!"K:AA:== B>D9)=:D=<>:,!M6F:>):AD:1E:')B=:'!D9BAO:?!B>:!B=!B!EB6)E<E :=!BC,!+%0/`!dBAD:''B!:=!BC,!#$$/&Q!O:A:=)D!"eBEF(A!:=!BC, '<>)AO!B!F>:':=:>E)A:'!=)E:![)A'([!DBCC:'!=9:!D>)=)DBC #$$$&Q! YB?D<CB>! "KCBDN! :=! BC,! +%42`! G)>:YBBO! :=!BC,! +%44` F:>)('!"K:>B>')!:=!BC,!#$$$`!S:A?D9Q!#$$3&Q![9)D9!)A!=9:!>B= ;>OBA'(PB!f!WBI<:A=:Q!+%%0Q!#$$$`!;>OBA'(PB!:=!BC,!#$$3` sábado 29 de mayo de 2010 K:AO(:=6:B!:=!BC,!#$$4&!BA'!B?=>(OC)BC!"d(>Y:==)!:=!BC,!#$$5Q
  159. 159. sábado 29 de mayo de 2010
  160. 160. Patología SNC TCE Ictus Tumores Patologías neurodegenerativas sábado 29 de mayo de 2010
  161. 161. Patología SNC TCE Ictus Tumores Patologías neurodegenerativas Vascularización sábado 29 de mayo de 2010
  162. 162. Neuroprotección mediante enriquecimiento ambiental Patologías neurodegenerativas Parkinson Alzheimer Hungtinton Ictus TCE sábado 29 de mayo de 2010
  163. 163. Objetivos terapeúticos Neuroprotección/neurorescate Incremento vascularización sábado 29 de mayo de 2010
  164. 164. TCE en Desarrollo Mayor capacidad de plasticidad Interferencia en los mecanismos fisiológicos Apoptosis Plasticidad sináptica (NMDA) sábado 29 de mayo de 2010
  165. 165. Current research Effects of VEGF administration and inhibition in the visual cortex of developing rats sábado 29 de mayo de 2010
  166. 166. Current research Effects of VEGF administration and inhibition in the visual cortex of developing rats sábado 29 de mayo de 2010
  167. 167. VEGF infusion 18 dpn Long Evans rats Alzet minipumps for 1 week at a 1 µl /h rate. VEGF. 25 ng/ml. anti-VEGF. 25 µg/ml. PBS. Untreated rats. sábado 29 de mayo de 2010
  168. 168. sábado 29 de mayo de 2010
  169. 169. Minipump placement sábado 29 de mayo de 2010
  170. 170. sábado 29 de mayo de 2010
  171. 171. sábado 29 de mayo de 2010
  172. 172. Vascular density sábado 29 de mayo de 2010
  173. 173. Vascular density sábado 29 de mayo de 2010
  174. 174. Vascular density 50,0 46 46 37,5 38 35 31 30 29 25,0 26 26 27 12,5 0 18 dpn PBS aVEGF VEGF 25 dpn 18 dpn PBS aVEGF VEGF 25 dpn Ipsilateral cortex Contralateral cortex sábado 29 de mayo de 2010
  175. 175. Neuronal density sábado 29 de mayo de 2010
  176. 176. Neuronal Density (Optical dissector) sábado 29 de mayo de 2010
  177. 177. Neuronal Density (Optical dissector) sábado 29 de mayo de 2010
  178. 178. Neuronal density 0.000 102.158 95.775 90.520 90.520 2.500 86.608 86.542 85.839 82.161 82.161 75.425 5.000 27.500 0 18 dpn PBS aVEGF VEGF 25 dpn 18 dpn PBS aVEGF VEGF 25 dpn Ipsilateral cortex Contralateral cortex sábado 29 de mayo de 2010
  179. 179. Caspase-3 sábado 29 de mayo de 2010
  180. 180. Caspase-3 sábado 29 de mayo de 2010
  181. 181. C VEGF-SC-SC VEGF-SC-EE VEGF-EE-SC 110.000 82.500 Neuronal Density 55.000 * * * 27.500 * 0 IL CL sábado 29 de mayo de 2010
  182. 182. C VEGF-SC-SC VEGF-SC-EE VEGF-EE-SC 22.000 16.500 Apoptotic Density 11.000 * * * 5.500 * * 0 IL CL sábado 29 de mayo de 2010
  183. 183. Densidad vascular 2.000 21.694 21.694 20.075 18.149 18.344 18.149 17.852 16.500 16.935 11.000 5.500 0 Control EA Lesion Lesion EA Control EA Lesion Lesion EA Ipsilateral cortex Contralateral cortex sábado 29 de mayo de 2010

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