Blood-Brain Barrier and Immune Cell Transmigration: VEGF Signaling Pathways

Click on one of the other molecules below to see the signaling pathways activated by that molecule and the changes it induces in the integrity of the blood-brain barrier (BBB). Click on Overview to see the generalized process of immune cell transmigration across the BBB during neuroinflammation.

VEGF
VEGF
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VEGF R2/KDR
VEGF R2/KDR
PLC-gamma
PLC-gamma
PIP2
PIP2
DAG
DAG
PKC-beta
PKC-beta
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Occludin
Occludin
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ZO-1
ZO-1
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ZO-2
ZO-2
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F-Actin
F-Actin
AKR1B10
AKR1B10
ITCH/AIP4
ITCH/AIP4
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Esp15
Esp15
Epsin-1
Epsin-1
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Proteosomal
Degradation

Proteosomal
Degradation

ZO-1
ZO-1
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Afadin/AF-6
Afadin/AF-6
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Claudins
Claudins
ZO-1
ZO-1
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Afadin/AF-6
Afadin/AF-6
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JAMs
JAMs
Cingulin
Cingulin
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VE-Cadherin
VE-Cadherin
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p120
p120
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beta-Catenin
beta-Catenin
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alpha-Catenin
alpha-Catenin
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IP3
IP3
IP3 Receptor
IP3 Receptor
Ca2+
Ca2+
Ca2+/Calmodulin
Ca2+/Calmodulin
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eNOS
eNOS
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Occludin
Occludin
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Claudin-5
Claudin-5
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MLC2
MLC2
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Stress Fiber Formation
Increased Centripetal Tension
Cell Retraction

Stress Fiber Formation
Increased Centripetal Tension
Cell Retraction

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SH2D2A
SH2D2A
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Src
Src
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Vav-2
Vav-2
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Rac
Rac
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PAK
PAK
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Occludin
Occludin
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ZO-1
ZO-1
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ZO-2
ZO-2
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F-Actin
F-Actin

Receptor Endocytosis

Receptor Endocytosis

ZO-1
ZO-1
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Afadin/AF-6
Afadin/AF-6
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Claudins
Claudins
JAMs
JAMs
Cingulin
Cingulin
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VE-Cadherin
VE-Cadherin
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p120
p120
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beta-Catenin
beta-Catenin
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alpha-Catenin
alpha-Catenin
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VE-Cadherin
VE-Cadherin
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Receptor Endocytosis

Receptor Endocytosis

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alpha-Catenin
alpha-Catenin
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p120
p120
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PI 3-Kinase
PI 3-Kinase
Akt
Akt
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FoxO1/FKHR
FoxO1/FKHR
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beta-Catenin
beta-Catenin
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FoxO1/FKHR
FoxO1/FKHR
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TCF/LEF
TCF/LEF
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Claudin-5
Claudin-5
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Brain Tissue
Brain Tissue
Brain Endothelial Cells
Brain Endothelial Cells

Overview of VEGF Signaling and its Primary Biological Effects in Brain Endothelial Cells

The BBB is a selective diffusion barrier that is composed of specialized endothelial cells (ECs) that are linked by tight junctions (TJs) and adherens junctions (AJs). These junction complexes can be remodeled during neuroinflammation to form interendothelial gaps that peripheral immune cells will pass through to enter the central nervous system (CNS). VEGF is elevated in the CNS during neuroinflammatory conditions and is a potent inducer of BBB disruption. VEGF binds to its receptor on brain ECs to initiate intracellular signaling cascades that result in the dynamic reorganization of junction complexes and EC retraction. VEGF induces the phosphorylation of TJ proteins, resulting in their disassembly and/or redistribution from the cell border. Specifically, VEGF promotes endocytosis of Occludin and VE-Cadherin. Additionally, VEGF induces degradation of Occludin by the Ubiquitin-proteasome pathway. VEGF has also been shown to down-regulate the expression of Occludin and Claudin-5, and induce reorganization of F-Actin microfilaments into stress fibers, which increases centripetal tension inside the cell resulting in cell retraction.

To learn more, please visit our VEGF Family Research Area.

Blood-Brain Barrier and Immune Cell Transmigration: VEGF Signaling Pathways background image 1