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  • Review Article
  • Published:

Mechanisms and regulation of endothelial VEGF receptor signalling

Nature Reviews Molecular Cell Biology volume 17, pages 611–625 (2016)Cite this article

Subjects

Key Points

  • Vascular endothelial growth factor receptor (VEGFR) signalling is tightly regulated at different levels: ligand and receptor expression, the presence of co-receptors and accessory proteins (that is, neuropilins, proteoglycans and integrins, among others) and inactivating tyrosine phosphatases. Together, these control the rate of cellular uptake, degradation and recycling.

  • Canonical versus non-canonical signalling indicates VEGF-dependent versus non-VEGF-dependent activation of VEGFR2. Among the latter are mechanical forces, gremlins, galectins, lactate and low-density lipoprotein (LDL) cholesterol.

  • VEGFR signalling output is regulated by crosstalk with numerous receptor systems, including fibroblast growth factor receptor (FGFR), AXL, Delta–Notch and Hippo pathways.

  • VEGFR2 endocytosis and subsequent cytoplasmic trafficking have a key role in regulation of ERK signalling, which is crucial for numerous VEGF biological activities, including arterial fate determination, proliferation and migration.

  • VEGF-dependent regulation of permeability involves T cell-soecific adapter (TSAd) and junctional SRC activation and crosstalk with AXL-dependent PI3K activation.

  • Protein tyrosine phosphatases have important roles in regulation of specific VEGFR2-activated intracellular signalling events.

Abstract

Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are uniquely required to balance the formation of new blood vessels with the maintenance and remodelling of existing ones, during development and in adult tissues. Recent advances have greatly expanded our understanding of the tight and multi-level regulation of VEGFR2 signalling, which is the primary focus of this Review. Important insights have been gained into the regulatory roles of VEGFR-interacting proteins (such as neuropilins, proteoglycans, integrins and protein tyrosine phosphatases); the dynamics of VEGFR2 endocytosis, trafficking and signalling; and the crosstalk between VEGF-induced signalling and other endothelial signalling cascades. A clear understanding of this multifaceted signalling web is key to successful therapeutic suppression or stimulation of vascular growth.

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Figure 1: VEGFR2 structure and receptor signalling complexes.
Figure 2: VEGFR2 signal transduction pathways.
Figure 3: Regulation of VEGFR2 signalling by receptor crosstalk.
Figure 4: Plasma membrane versus endocytic VEGFR2 signalling.

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Acknowledgements

The authors gratefully acknowledge the following agencies for support of their work: grants from the Swedish Science Council, Swedish Cancer Foundation, World-wide Cancer Research and the Knut and Alice Wallenberg Foundation (L.C.-W.); US National Institutes of Health (NIH) grants R01 HL053793, HL084619 and P01 HL107205 (M.S.); and a Wenner–Gren foundation grant (E.G.). The authors also thank their colleagues at Yale Cardiovascular Research Center (YCVRC) and Uppsala University, as well as close colleagues around the world, for productive discussions and advice.

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  1. Yale Cardiovascular Research Center, 300 George St, New Haven, 06511, Connecticut, USA

    Michael Simons

  2. Department of Immunology, Uppsala University, Genetics and Pathology, Rudbeck Laboratory and Science for Life Laboratory, Dag Hammarskjöldsv 20, Uppsala, 751 85, Sweden

    Emma Gordon & Lena Claesson-Welsh

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Glossary

Receptor tyrosine kinases

Cell surface receptors that, on binding ligands, dimerize and undergo a conformation change that activates intracellular tyrosine kinase, leading to tyrosine phosphorylation of the receptor's intracellular domain as well as signal transducers.

Neuropilins

(NRPs). Transmembrane glycoproteins that can bind to vascular endothelial growth factors (VEGFs) and semaphorins and act either as receptors or co-receptors (together with VEGF receptors and plexins) to modulate intracellular signalling.

Heparan sulfate proteoglycans

(HSPGs). Proteoglycans carrying heparan sulfate chains that can bind to various heparin-binding growth factors found on the plasma membrane or the extracellular matrix. They can function as vascular endothelial growth factor co-receptors or signal independently.

Integrins

Transmembrane receptors that link the extracellular matrix to the cell and transmit signals to communicate the characteristics of the surrounding environment across the membrane.

Extracellular matrix

(ECM). The non-cellular component of tissues and organs comprising proteins and carbohydrates that provide structural and biochemical support for cellular structures.

Semaphorins

Secreted or membrane-bound guidance proteins that control cell movement through multimeric cognate receptor complexes.

Focal adhesions

Contact points between the cell and the extracellular matrix comprising integrins and actin filament bundles.

Tetraspanin

Transmembrane-4 glycoproteins that interact both with themselves and with other transmembrane receptors to regulate various cellular processes, such as fusion, receptor trafficking and motility.

VE-cadherin

Adherens junction type II cadherin expressed on endothelial cells and localized at cell–cell junctions. Involved in the regulation of vascular integrity and permeability.

Tip cells

Highly migratory endothelial cells with polarized filopodial extensions at the leading position of the growing angiogenic sprout.

Stalk cells

Highly proliferative endothelial cells that follow tip cells and contribute to the elongation, lumenization and stabilization of the nascent sprout.

Lipid rafts

Specialized, dynamically assembled regions of the membrane enriched in certain proteins and lipids.

Clathrin-enriched pits

Invaginations in the plasma membrane assembled by the growth of a clathrin lattice that are involved in receptor endocytosis.

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Simons, M., Gordon, E. & Claesson-Welsh, L. Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol 17, 611–625 (2016). https://doi.org/10.1038/nrm.2016.87

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