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Vascular Endothelial Growth Factor-A-Induced Vascular Permeability and Leukocyte Extravasation

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Endothelial Signaling in Development and Disease

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Abstract

This review describes the process of vascular endothelial growth factor-A (VEGFA)-induced vascular permeability. A consequence of this response is edema formation and we briefly touch upon the mechanisms operating in endothelial cells that underlie leakage of plasma into tissue. We also describe signal transduction pathways downstream of the VEGF receptor-2 responsible for the in vivo permeability response. These involve the signaling molecules Src family kinases, Axl, focal adhesion kinase (FAK), phosphatidyl-inositol 3´kinase (PI3K), Akt, Rac, endothelial nitric oxide synthase (eNOS), and the adapter molecules TSAd, Shb, GAB1 and IQGAP1. Specific mechanisms for leukocyte extravasation in this context will be described. Despite the wealth of data characterizing the mechanisms of VEGFA-induced vascular permeability, the precise functional significance of this response for physiological processes remains elusive, although it is assumed that it promotes neoangiogenesis and tissue repair after ischemia.

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Abbreviations

VEGFA:

Vascular endothelial growth factor A

VEGFR:

Vascular endothelial growth factor receptor

FAK:

Focal adhesion kinase

PI3K:

Phosphatidyl-inositol 3´kinase

eNOS:

Endothelial nitric oxide synthase

TSAd:

T cell-specific adapter protein

Shb:

Src homology-2 domain protein B

GAB1:

Grb2-associated binding protein 1

IQGAP1:

IQ motif-containing GTPase activating protein 1

VVOs:

Vesiculo-vacuolar organelles

VE-cadherin:

Vascular endothelial-cadherin

NO:

Nitric oxide

PAK:

p21-activated kinase

HGF:

Hepatocyte growth factor

N-WASP:

Neural Wiskott–Aldrich syndrome protein

Tiam:

T-cell lymphoma invasion and metastasis

VE-PTP:

Vascular endothelial -protein tyrosine phosphatase

ERK:

Extracellular signal-regulated kinase

CXCR:

Chemokine C-X-C motif ligand receptor

MMP:

Matrix metalloproteinase

ICAM-1:

Intercellular adhesion molecule-1

PSGL1:

P-selectin glycoprotein ligand 1

SDF-1:

Stromal cell-derived factor-1

ROS:

Reactive oxygen species

BRB:

Blood-retinal barrier

RCE:

Retinal capillary cell

RPE:

Retinal pigment epithelial cell

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Acknowledgments

The study was supported by grants from Diabetes Wellness Sweden (MP), the Novo Nordisk foundation (MP), the Swedish Cancer Fund (MW, LCW), the Swedish Research Council (MP, MW, LCW), the Swedish Diabetes Fund (MP, MW), the Ragnar Söderberg foundation (MP), the Knut and Alice Wallenberg Foundation (MP, LCW), and the Family Ernfors Fund (MP, MW).

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Authors and Affiliations

  1. Department of Medical Cell Biology, Uppsala University, Husargatan 3, P.O. Box 571, 75123, Uppsala, Sweden

    Mia Phillipson PhD, Dr. Gustaf Christoffersson PhD & Prof. Michael Welsh PhD

  2. Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjöldsv. 20, 75185, Uppsala, Sweden

    Prof. Dr. Lena Claesson-Welsh

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  1. Mia Phillipson PhD
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  2. Dr. Gustaf Christoffersson PhD
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  3. Prof. Dr. Lena Claesson-Welsh
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  4. Prof. Michael Welsh PhD
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Correspondence to Michael Welsh PhD .

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  1. Microscopic Anatomy and Neurobiology Building 708, 2.Floor, R2.006, Johannes Gutenberg University School of Medicine, Mainz, Germany

    Mirko HH Schmidt

  2. Institute of Neurology Building 89, 4.Floor, R402, Goethe University Frankfurt School of Medicine, Frankfurt, Germany

    Stefan Liebner

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Phillipson, M., Christoffersson, G., Claesson-Welsh, L., Welsh, M. (2015). Vascular Endothelial Growth Factor-A-Induced Vascular Permeability and Leukocyte Extravasation. In: Schmidt, M., Liebner, S. (eds) Endothelial Signaling in Development and Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2907-8_8

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