Cerebral Vascularization Guide

Vascularización
cerebral

Laboratorio de Neurociencia
Clínica y Experimental (LaNCE)
Euskal Herriko Unibertsitatea
http://www.ehu.es/ehusfera/lance

viernes 29 de octubre de 2010

Vascularización
cerebral

Enrike G. Argandoña
Laboratorio de Neurociencia
Clínica y Experimental (LaNCE)
Euskal Herriko Unibertsitatea
http://www.ehu.es/ehusfera/lance


Vascularización cerebral

2


Sistema arterial aferente

2


Sistema arterial aferente
Sistema venoso eferente

2


3


1% volumen cerebral

3


1% volumen cerebral
20% Gasto cardiaco

3


1% volumen cerebral
20% Gasto cardiaco
65% consumo energía
3


5


Control de la circulación sistémica

5


Autorregulación vascularización
cerebral

5


Autorregulación vascularización
cerebral
Distribución del ﬂujo

5

14



17


Vascularización intracerebral

30


Arteriolas (50-100 µm)

30


Arteriolas terminales (10-100µm)

30


Vénulas (± 30 µm)

30


Vénulas (± 30 µm)
Capilares (<30 µm)

30

Vascularización cortical
Red capilar
640 km (reducida en Alzheimer)
Un capilar por neurona

Barrera hematoencefálica
Mecanismos estructurales
Mecanismos metabólicos


Barreras cerebrales


33



34



Tipos de transporte

Texto


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-soluble

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

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
interaction domain (MAGI) are examples of second-order adaptor molecules. The first- and second-order adaptor molecules together with signaling molecu

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
viernes 29 de octubre de 2010 buffer) when neural activity ceases. Astrocytes can also Pgp on astrocytes and brain endothelium98,99; this may
+ + +

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
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

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.
function. bradykinin, produced during inflammation in stroke or brain trauma, acts on

41

Endotelio cerebral


41

Endotelio cerebral

Rico en mitocondrias


41

Endotelio cerebral

Ausencia de pinocitosis


41

Endotelio cerebral

Ausencia de pinocitosis
Ausencia de fenestraciones


l. Encircling the basal lamina of
42
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).

43

Astroglia


43

Astroglia
Inducción de la
BHE


43

Astroglia
Inducción de la
BHE
Mantenimiento de
la BHE


43

Astroglia
Inducción de la
BHE
Mantenimiento de
la BHE
Control del tono
vascular


43

Astroglia
Inducción de la
BHE
Mantenimiento de
la BHE
Control del tono
vascular
Estructura de la
BHE?


44

Pericitos


44

Pericitos

Identidad oscura
Células
pluripotenciales
Participación en
inducción y
maduración de la
BHE


LETTER
45
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 inPdgfbret/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 in
viernes 29 de complemented by one or two copies of a conditionally silent
alleles were octubre de 2010 endothelial cells and in the brain parenchyma in Pdgfbret/ret and

LETTER
45
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 inPdgfbret/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 in
viernes 29 de complemented by one or two copies of a conditionally silent
alleles were octubre de 2010 endothelial cells and in the brain parenchyma in Pdgfbret/ret and

Uniones densas (TJ)


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

50

Actina


51

Células


51

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.
viernes 29 de octubre decells express a number of transporters and receptors, some of which are shown. EAAT1–3, excitatory amino acid
2010

52

Regulación de la permeabilidad
vascular


53

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
sel wall can sense signals from neurons (arrow 2). Activated endothelium, microglia, and astrocytes signal back to neurons, which in most cases agg

54

Red capilar


Desarrollo vascular

Extracraneal
Intracraneal
Troncos perpendiculares
Arborización


Desarrollo vascular


0 dpn

60

7 dpn

61

14 dpn

62

21 dpn

63

60 dpn

64

VEGF
Vascular Endothelial Growth Factor

I. Inductor de:
• Proliferación endotelial
• Migración endotelial
• Inhibición apotosis

II. Efectos neurotróﬁcos
y neuroprotectores

III. Permeabilidad
vascular


VEGF
Vascular Endothelial Growth Factor


VEGF en angiogénesis

68

VEGF en angiogenesis


Neuroproteccion
VEGF en


VEGF
Efectos neurotróﬁcos


VEGF
Hiperpermeabilidad
ZO-1 VEGF Actina


Angiogénesis


Mechanism of BOLD Functional MRI
Brain activity

Oxygen consumption Cerebral blood flow

Oxyhemoglobin
Deoxyhemoglobin

Magnetic susceptibility

T2*

MRI signal intesity


Oxyhemoglobin and
Deoxyhemoglobin in Veins during
Brain Activation
Rest Activation

Normal blood flow High blood flow

Oxyhemoglobin
Deoxyhemoglobin


Signal Intensity
Time Series and Activation Maps

Off On Off On Off On Off On

Scan Number


Multi-Slice Spiral Images


Multi-Slice EPI Images


Activation Maps on Anatomical
Images

MS
Spiral

MS
EPI

3D
Spiral


Visual Activation Maps (ISI=12s)


All images courtesy of Johann Wolfgang G oethe University Hospital,

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

Neural correlates of admiration and compassion.
Immordino-Yang MH, McColl A, Damasio H, Damasio A. Proc Natl Acad Sci U S A. 2009 May
12;106(19):8021-6.

Angiogénesis y
neurogénesis
Dos caminos paralelos


Desarrollo cortical

Predeterminado genéticamente
Mediado por experiencia


Desarrollo cortical

Predeterminado genéticamente
Mediado por experiencia

PERIODO CRÍTICO
3ª - 5ª semanas


Neurogenesis Angiogenesis

?


Neurogenesis Angiogenesis

Nicho vascular (neurogenesis). Palmer 2000.

Incremento demanda. Black 1987.

Coordinados. Carmeliet 2005.


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)


Neuroscience 171 (2010) 214 –226

ANGIOGENESIS BUT NOT NEUROGENESIS IS CRITICAL et al. / Neuroscience 171 (2010) 214 –226
A. L. Kerr FOR
NORMAL LEARNING AND MEMORY ACQUISITION
A. L. KERR,1 E. L. STEUER, V. POCHTAREV AND cognitive performance on a variety of tasks including the
R. A. SWAIN* Morris water maze (MWM), contextual fear conditioning,
University of Wisconsin-Milwaukee, Milwaukee, WI, USA extinction of contextual fear, and radial arm maze (Ander-
son et al., 2000; Baruch et al., 2004; Fordyce and Wehner,
1993; Gobbo and O’Mara, 2004; Pietropaolo et al., 2006;
Abstract—Aerobic exercise has been well established to pro-
mote enhanced learning and memory in both human and Powell, 2005; Vaynman et al., 2004). In humans, exercise
non-human animals. Exercise regimens enhance blood per- has been associated with improved cognitive performance in
fusion, neo-vascularization, and neurogenesis in nervous young adult, aging adult, and brain-injured populations
system structures associated with learning and memory. The (Churchill et al., 2002; Grealy et al., 1999; Kramer and Erick-
impact of specific plastic changes to learning and memory son, 2007; Kramer et al., 2006; Winter et al., 2007) and has
performance in exercising animals are not well understood. been shown to protect against the onset of various demen-
The current experiment was designed to investigate the con-
tias, including Alzheimer’s disease (Laurin et al., 2001).
tributions of angiogenesis and neurogenesis to learning and
memory performance by pharmacologically blocking each The means by which experience facilitates learning
process in separate groups of exercising animals prior to and memory are not fully understood. However, the sur-
visual spatial memory assessment. Results from our experi- vival of new neurons may contribute to learning and mem-
ment indicate that angiogenesis is an important component ory changes following exercise. It has been consistently
of learning as animals receiving an angiogenesis inhibitor shown that both enriched environments and exercise (vol-
exhibit retarded Morris water maze (MWM) acquisition. Inter- untary and forced) promote neurogenesis in the adult hip-
estingly, our results also revealed that neurogenesis inhibi-
pocampus, specifically in the dentate gyrus (DG) (Christie
tion improves learning and memory performance in the
MWM. Animals that received the neurogenesis inhibitor dis-
et al., 2008; Kempermannn et al., 1997, 1998; Kim et al.,
played the best overall MWM performance. These results 2002; Olson et al., 2006; Uysal et al., 2005; Van der Borght
point to the importance of vascular plasticity in learning and et al., 2006; van Praag et al., 2005), and exercise-induced
memory function and provide empirical evidence to support neurogenesis is correlated with improved learning and mem-
the use of manipulations that enhance vascular plasticity to ory performance (Uysal et al., 2005; van Praag et al., 2005).
improve cognitive function and protect against natural cog- However, there are also reports that manipulation of neuro-
nitive decline. © 2010 IBRO. Published by Elsevier Ltd. All
genesis does not impact learning and memory function in the
rights reserved.
MWM (Meshi et al., 2006; Shors et al., 2002) or contextual
Key words: vascular plasticity, exercise-induced facilitation, fear conditioning (Clark et al., 2008; Shors et al., 2002),
Morris water maze. indicating that neurogenesis may not be the sole supporter of
enhanced cognitive performance following exercise.
The contribution of neurogenesis to learning and mem-
Aerobic exercise promotes enhanced learning and memory function is further complicated by recent evidence sug-
ory in both human and non-human animals. At the cellular gesting that newly proliferated neurons are not immedi-
level, exercise is associated with increased angiogenesis ately and functionally incorporated into existing learning
(the sprouting of new capillaries from preexisting blood networks. While it is clear that new neurons do become
vessels) and/or neurogenesis in various areas of the brain functionally integrated into the existing circuitry eventually,
including the hippocampus, motor cortex and cerebellum several recent reports indicate that this integration is a
(Black et al., 1991; Clark et al., 2009; Isaacs et al., 1992; somewhat delayed process taking between 3 and 4 weeks
Kim et al., 2002; Sikorski et al., 2008; Swain et al., 2003; to complete (Kee et al., 2007; Overstreet et al., 2004; van
van Praag et al., 2005). Aerobic exercise in rodents is also Praag et al., 2002). These data are supported by behav-
associated with improved recovery following ischemic in- ioral studies indicating that impaired neurogenesis does
sult (Lee et al., 2003a,b; Sim et al., 2004) and improved not affect visual spatial memory in the MWM immediately
1
Present address: University of Texas, Austin, TX, USA. following treatment but impairs performance when memory
*Corresponding author. Tel: 1-414-229-5883; fax: 1-414-229-5219. is tested 28 days later (Hu et al., 2008).
viernes 29 de rswain@uwm.edu (R. A. Swain). 4.AZT-injected vol-
E-mail address:
octubre de 2010AZT-VX, BrdU quantification and NeuN colabel. Tissue was treated with immunohistochemical antibodies targeting BrdU to label dividing cells (indi
Abbreviations: ABC, avidin-biotin complex; Fig.
The current experiment investigated the relative con-

Neuroscience 171 (2010) 214 –226

ANGIOGENESIS BUT NOT NEUROGENESIS IS CRITICAL FOR
NORMAL LEARNING AND MEMORY ACQUISITION
A. L. KERR,1 E. L. STEUER, V. POCHTAREV AND cognitive performance on a variety of tasks including the
R. A. SWAIN* Morris water maze (MWM), contextual fear conditioning,
University of Wisconsin-Milwaukee, Milwaukee, WI, USA extinction of contextual fear, and radial arm maze (Ander-
son et al., 2000; Baruch et al., 2004; Fordyce and Wehner,
1993; Gobbo and O’Mara, 2004; Pietropaolo et al., 2006;
Abstract—Aerobic exercise has been well established to pro-
mote enhanced learning and memory in both human and Powell, 2005; Vaynman et al., 2004). In humans, exercise
non-human animals. Exercise regimens enhance blood per- has been associated with improved cognitive performance in
fusion, neo-vascularization, and neurogenesis in nervous young adult, aging adult, and brain-injured populations
system structures associated with learning and memory. The (Churchill et al., 2002; Grealy et al., 1999; Kramer and Erick-
impact of specific plastic changes to learning and memory son, 2007; Kramer et al., 2006; Winter et al., 2007) and has
performance in exercising animals are not well understood. been shown to protect against the onset of various demen-
The current experiment was designed to investigate the con-
tias, including Alzheimer’s disease (Laurin et al., 2001).
tributions of angiogenesis and neurogenesis to learning and
memory performance by pharmacologically blocking each The means by which experience facilitates learning
process in separate groups of exercising animals prior to and memory are not fully understood. However, the sur-
visual spatial memory assessment. Results from our experi- vival of new neurons may contribute to learning and mem-
ment indicate that angiogenesis is an important component ory changes following exercise. It has been consistently
of learning as animals receiving an angiogenesis inhibitor shown that both enriched environments and exercise (vol-
exhibit retarded Morris water maze (MWM) acquisition. Inter- untary and forced) promote neurogenesis in the adult hip-
estingly, our results also revealed that neurogenesis inhibi-
pocampus, specifically in the dentate gyrus (DG) (Christie
tion improves learning and memory performance in the
MWM. Animals that received the neurogenesis inhibitor dis-
et al., 2008; Kempermannn et al., 1997, 1998; Kim et al.,
played the best overall MWM performance. These results 2002; Olson et al., 2006; Uysal et al., 2005; Van der Borght
point to the importance of vascular plasticity in learning and et al., 2006; van Praag et al., 2005), and exercise-induced
memory function and provide empirical evidence to support neurogenesis is correlated with improved learning and mem-
the use of manipulations that enhance vascular plasticity to ory performance (Uysal et al., 2005; van Praag et al., 2005).
improve cognitive function and protect against natural cog- However, there are also reports that manipulation of neuro-
nitive decline. © 2010 IBRO. Published by Elsevier Ltd. All
genesis does not impact learning and memory function in the
rights reserved.
MWM (Meshi et al., 2006; Shors et al., 2002) or contextual
Key words: vascular plasticity, exercise-induced facilitation, fear conditioning (Clark et al., 2008; Shors et al., 2002),
Morris water maze. indicating that neurogenesis may not be the sole supporter of
enhanced cognitive performance following exercise.
The contribution of neurogenesis to learning and mem-
Aerobic exercise promotes enhanced learning and memory function is further complicated by recent evidence sug-
ory in both human and non-human animals. At the cellular gesting that newly proliferated neurons are not immedi-
level, exercise is associated with increased angiogenesis ately and functionally incorporated into existing learning
(the sprouting of new capillaries from preexisting blood networks. While it is clear that new neurons do become
vessels) and/or neurogenesis in various areas of the brain functionally integrated into the existing circuitry eventually,
including the hippocampus, motor cortex and cerebellum several recent reports indicate that this integration is a
(Black et al., 1991; Clark et al., 2009; Isaacs et al., 1992; somewhat delayed process taking between 3 and 4 weeks
Kim et al., 2002; Sikorski et al., 2008; Swain et al., 2003; to complete (Kee et al., 2007; Overstreet et al., 2004; van
van Praag et al., 2005). Aerobic exercise in rodents is also Praag et al., 2002). These data are supported by behav-
WM one probe trials. (A) All animals ischemic equivalentstudies indicating time in the correct quadrant during the first probe trial. (B) All animals
associated with improved recovery following spent in- ioral amounts of that impaired neurogenesis does
sult (Lee et al., 2003a,b; Sim et al., 2004) and improved not affect visual spatial memory in the MWM immediately
ilar amounts of time in the SW quadrant, which is directlytreatment but impairs performance when memory represents the greatest distance from the plat
1
Present address: University of Texas, Austin, TX, USA. following
opposite the target quadrant and
als can search.author. Tel: 1-414-229-5883; fax: 1-414-229-5219. trial, SU5416-VX later (Hu et al., 2008).
*Corresponding (C) During the remote probe is tested 28 days and VEH-IC animals spent significantly less time in the correct quadrant
viernes 29 de octubre de 2010Swain).
E-mail address: rswain@uwm.edu (R. A.
The current experiment investigated the relative con-

Sistema visual
Sistema Visual


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


Empobrecimiento ambiental

Descenso densidades neuronal,
glial y vascular
Retraso maduración
Anulación cierre periodo
crítico


Empobrecimiento ambiental


Cortical parameters


Vascular density


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


Enriquecimiento ambiental
Donald Hebb (1949)

Kresh, Bennett, Rosenzweig, Diamond (60s)
Combinación de complejidad de objetos
inanimados y estimulación social.

Cambios anatómicos
Plasticidad neuronal
Sinaptogénesis
Morfología sináptica
Neurogénesis
Neurotroﬁnas (BDNF, NGF, NT-3,VEGF)

Gliogénesis

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)



Edades :

. 14 dpn, 21 dpn Pre-critical

. 28 dpn, 35 dpn, 42 dpn Critical period

. 49 dpn, 56 dpn, 63 dpn Postcritical


Estudio cualitativo

Inmunohistoquimia Histoquimia
LEA

EBA

GluT-1

LEA EBA
Estudio cualitativo


Estudio cualitativo EBA GluT-1

EBA + GluT-1



Angiogénesis


Estudio cuantitativo


VEGF

WESTERN BLOT

ELISA


ELISA


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

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viernes 29 de octubre de 2010 K:AO(:=6:B!:=!BC,!#$$4&!BA'!B?=>(OC)BC!"d(>Y:==)!:=!BC,!#$$5Q

Patología SNC
TCE
Ictus
Tumores
Patologías neurodegenerativas


Patología SNC
TCE
Ictus
Tumores
Vascularización


Neuroprotección mediante
enriquecimiento ambiental
Parkinson
Alzheimer
Hungtinton
Ictus
TCE

Objetivos terapeúticos

Neuroprotección/neurorescate
Incremento vascularización


TCE en Desarrollo
Mayor capacidad de plasticidad
Interferencia en los
mecanismos ﬁsiológicos
Apoptosis
Plasticidad sináptica (NMDA)


Current research

Effects of VEGF
administration and inhibition
in the visual cortex of
developing rats


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.


Minipump placement


EBA


HSP-70


GFAP


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

Neuronal density


Neuronal Density
(Optical dissector)


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


Caspase-3


C VEGF-SC-SC VEGF-SC-EE VEGF-EE-SC

110.000

82.500
Neuronal Density

55.000
*
* *
27.500 *

0
IL CL


C VEGF-SC-SC VEGF-SC-EE VEGF-EE-SC

22.000

16.500
Apoptotic Density

11.000

*
* *
5.500 * *

0
IL CL


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


[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

Contacto

www.slideshare.net/nfpguare

www.ehu.es/ehusfera/lance

eg.argandona@ehu.es


Cerebral Vascularization Guide

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