Capillaries in Most Tissues (e.g.

Muscle)

Blood in
capillary
lumen

Spaces between
adjacent endothelial
cells
Not so tight, Gap
junctions

Muscle Cells
Tissue Fluid (ISF)

Weve got free pass.

Why bother to go find that
narrow gap!

Blood in
capillary
lumen

Gases, water, lipid

soluble substances.
E.g. Steroids, fatty
acids etc.

Muscle Cells
Tissue Fluid (ISF)

Glucose, amino acids,

Na+, Ca2+, H+, other
small hydrophilic
substances

Blood in
capillary
lumen

Im bouncing of

Down we
go!

Its
cool!

Tissue Fluid (ISF)

Muscle Cells

Blood in
capillary
lumen

Too
narrow to
squeeze
through

Proteins

No worries.
Theres
Genting cable
car

Muscle Cells
Tissue Fluid (ISF)

Wow!
What a
ride!

Proteins

n
Tra

Blood in
capillary
lumen

is
tos
scy

Tissue Fluid (ISF)

Muscle Cells

Capillaries in
Brain

Blood in
capillary
lumen

Spaces between
adjacent endothelial
cells
Very tight, Tight
junctions

WARNING
No Unauthorized
Entry
Tissue Fluid (ISF)

Nerve Cells

Proteins
Blood in
capillary
lumen

Glucose, amino acids,

Na+, Ca2+, H+, other
small hydrophilic
substances

No cable car
services. No
chance at all!

Gases, water, lipid

soluble substances.
E.g. Steroids, fatty
acids etc.

Cant go in!

Nerve Cells
Tissue Fluid (ISF)

Proteins

Glucose, amino acids,

Na+, Ca2+, H+, other
small hydrophilic
substances

Blood in I have totally given

up crossing this
capillary
wall!
lumen

Gases, water, lipid

soluble substances.
E.g. Steroids, fatty
acids etc.

There is another
barrier!

Foot Processes
of Astrocytes

Tissue Fluid

Foot Processes
(ISF)of Astrocytes

Nerve Cells

Mid gestation guinea pig embryo

injected
with
trypan
blue
(Wislocki, 1920)

Very early pig embryo (9mm,E19)

injected
with
isotonic
sodium
ferrocyanide into spinal canal (arrow)
treated
with
acid
(Prussian
blue
reaction) (From Weed, 1917)

EAAT13:
Excitatory Amino Acid
Transporters 13
GLUT1:
Glucose Transporter 1
LAT1:
L-system for Large
Neutral amino acids
Pgp: P-glycoprotein

Cellularinterplayattheneurovascularunit(capillarylevel). TheBBB
ispartoftheNVU,whichrepresentsanelaborateinterplayofcentral
andperipheralcells.
Vascular
endothelialcellssealedbytight
junctionsconstitutetheBBB.
The
endotheliums
abluminalsurfaceiscoveredbyabasement
membraneinwhich
pericytesandtheirprocessesareembedded.
Directintercellularcrosstalkbetween
endothelialcellsandpericytes
areimplementedbypeg-socketjunctions.Astrocytes
extendfoot
processesthatencircletheabluminalsideofthe vesseltoanextent

Molecular Composition of Endothelial Tight

Junctions

Pathways Across the BloodBrain Barrier

I. Angiogenesis and Barrier

Induction

Anorphan receptoris an apparentreceptorthat has a

similar structure to other identifiedreceptorsbut whose
endogenous ligand has not yet been identified. If a ligand for
anorphan receptoris later discovered, thereceptoris
referred to as an "adoptedorphan"
Neuralprogenitorcellssecrete
factorsthatguidesproutingendothelialcells.
VegfservesasacueforendothelialcellswhichexpressthereceptorFlk-1
NeuralprogenitorsecretedWntligandsbindFzdreceptorsonthe
endothelium,which
isrequiredformigrationofendothelialcellsintothe
embryonicneuraltissue
Wntsignalingalsoleadstothe transcription of BBB-related genes including
those encoding Glut-1 and TJ molecules
AngiogenicsproutingrequirestheendothelialorphanreceptorGpr124,which
regulates the migration of endothelial cells and expression of Glut-1

II. Interaction of CNS Endothelial cells with

Parenchymal cells to Seal the Barrier

Endothelialcellsofnascentvessels
release
Pdgf-bandtherebyrecruit
pericytesthat expressthereceptorPdgfrtothe endothelialsurface.
Interactionsbetweenendothelialcells
andpericytesaremediatedby
bidirectionalTgf-Tgf-Rsignaling,
leadingtotwomajoreffects.
First,upregulationofendothelial
cadherin-2leadstofirmadhesion
betweenendothelialcellsand
pericytes,and
second,pericytesarestimulatedto
depositECMcomponents,contributing
tobasementmembrane formation.

Whenpericytesaresetinplace,they
limitBBBpermeabilitybyproducingAng-1
thatsignalstoendothelialTie-2.
AstrocytesareinvolvedinlimitingBBB
permeabilitybythereleaseofShh,
whichactivatesHhsignalingin
endothelialcellsthroughthe recep- tor
Patched-1(Ptc1).
Furthermore,activatedSrc-suppressedCkinase
substrate(SSeCKS)inastrocytes
stimulates
Ang-1production,which
signalsbackto
endothelialTie-2
receptors.Theseinteractions
subsequentlyleadtothedevelopmentof
moreadvancedTJs,lossofleukocyte
adhesionmoleculesandinhibitionof

III. Maturation and

Maintenance
Sealingof
interendothelialTJsby
upregulationand redistributionofTJproteinsis
completedduring
maturationandneedsto
bemaintained.Wnt
ligandsfromanunknown
progenitorand astrocytes
regulateTJformation
throughtheFzdreceptor
expressedbyendothelial
cells.
CrosstalkbetweenendothelialcellsandpericytesmediatedbyTGF-TGF-Rand
Ang-1Tie-2signalingsupportsBBBformationandmaintenance.
SustainedBBBintegrityismainlyimplementedbyastrocytes.ApolipoproteinE
(ApoE) producedbyastrocytessignalsthroughLrp-1onbrainmicrovessels.It
hasalsobeenhypothesizedthatastrocyticApoEactsonpericytes,whichin
turnregulateendothelialTJs
EndothelialcellsupregulateTJproteinexpressionafteractivationbyShh
producedby
astrocytes.
Astrocyte-derivedAng-IIbindstoAT1receptorsonendothelialcellsand
promotestheformationandmaintenanceofinterendothelialTJs.

Central Role of Pericytes n

Neurovascular Unit

BBB
Breakdown
Causes

Characteristi
cs

Consequenc
es

BBB dysfunction and disturbed brain homeostasis:

Epilepsy

Epilepticseizurescanbepromotedbyluminalleukocyte-endothelial interactions,allowing
plasmaK+toentertheCNS,whichlowersthethresholdforseizures.Epileptogenic
inflammationduringandafter
seizuresissustainedbyastrocytesthatreleasecytokines
andchemokines(forexample,IL-6and CCL2).
MicrogliaandastrocytesproduceIL-1andVEGF,resultinginincreasedBBBpermeability
by
downregulationofendothelialZO-1.AcompromisedBBBleadstoleakageofplasma
componentsacrosstheendothelialcellmonolayer.IncreasedlevelsofK+andglutamate
(Glu)enhanceneuronexcitability. ExtravasatedalbuministakenupbyastrocytesviaTGFRandleadstoSmad2-mediated
downregulationoftheK+channelKir4.1;decreased
expressionofGlutransporterEAAT-2isinitiatedbyastrocyticTNF-.Bothmechanisms