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VEGF receptor signalling ? in control of vascular function

Key Points

  • Three vascular endothelial growth-factor receptors (VEGFRs) regulate vascular-endothelial, haematopoietic and lymphatic-endothelial cell function during development and in the adult. Many of these processes require balanced VEGFR signalling, which involves more than one of the VEGFRs.

  • VEGFR1 signalling seems to be dispensable for endothelial-cell function, but it is essential for the migration of haematopoietic cells. A soluble splice variant of VEGFR1, which lacks the intracellular domain, might function as a VEGF 'trap', and is implicated in preeclampsia during pregnancy. VEGFR1 signal transduction might positively or negatively regulate VEGFR2 activity.

  • VEGFR2 is absolutely required for endothelial-cell development and survival of blood vessels. Tyrosine phosphorylation sites in VEGFR2 regulate kinase activity and binding of phospholipase C-γ, and the adaptor molecules TSAd, Shb and Sck. VEGFR2-blocking therapies are in use or are being tested for the treatment of human malignancies.

  • VEGFR3 is required for cardiovascular development and lymphangiogenesis. Certain VEGF family members might induce formation of heterodimers, which involves VEGFR2 and VEGFR3, thereby regulating the phosphorylation of VEGFR3 and consequent signal transduction.

  • Co-receptors (VEGF-binding molecules that might lack intrinsic catalytic function) such as heparan-sulphate proteoglycans and neuropilins are engaged in the VEGFR signalling complex in a manner that is guided by the VEGF isoform. Co-receptors modulate the duration and quality of VEGFR signalling by the formation of VEGF gradients and by stabilizing the signalling complex. Cell?cell and cell?matrix adhesion molecules that are regulated, for example, by blood flow, affect VEGFR signalling by allowing receptor activation in the absence of VEGF.

  • The signal from an activated VEGFR is influenced by several factors (the particular VEGF isoform, the possibility of homodimerization or heterodimerization with other VEGFRs, co-receptors or adhesion molecules) in the local milieu.

Abstract

Vascular endothelial growth-factor receptors (VEGFRs) regulate the cardiovascular system. VEGFR1 is required for the recruitment of haematopoietic precursors and migration of monocytes and macrophages, whereas VEGFR2 and VEGFR3 are essential for the functions of vascular endothelial and lymphendothelial cells, respectively. Recent insights have shed light onto VEGFR signal transduction and the interplay between different VEGFRs and VEGF co-receptors in development, adult physiology and disease.

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Figure 1: VEGF receptor-binding properties and signalling complexes.
Figure 2: VEGFR phosphorylation sites and signal transduction.

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Acknowledgements

We thank colleagues and lab members for sharing their insights and for stimulating discussions. Owing to space limitations, we have not been able to cite all relevant work; we apologize to those whose work has been omitted. The authors are supported by the Swedish Research Council, the Swedish Cancer Foundation, the EU 6th framework program Lymphangiogenomics and Angiotargeting, the Association for International Cancer Research (to A.D.) and the Wenner?Gren Foundations (to J.K.).

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Glossary

Vasculogenesis

Establishment of the embryonic vascular system.

Angiogenesis

Formation of new blood vessels from already established vasculature.

Receptor tyrosine kinase

Single transmembrane growth-factor receptor with an intracellular enzymatic (tyrosine kinase) domain that is activated by growth-factor binding, resulting in the transfer of phosphate groups onto tyrosine residues.

Heparan sulphate proteoglycans

(HSPGs). Transmembrane, lipid-anchored or secreted proteins that interact, through covalently linked heparan sulphate chains, with many proteins, including VEGF.

Neuropilins

Transmembrane glycoproteins that have been characterized as receptors for semaphorins in neuronal guidance and as co-receptors for VEGFs in angiogenesis.

Oedema

Abnormal and excessive accumulation of fluid in the tissue, which might be localized or generalised.

Preeclampsia

A pregnancy disorder that is characterized by hypertension and proteinuria occurring after the 20th week of gestation.

Ascites

Accumulation of serous fluid in the peritoneal cavity.

Caveolae

Specialized micro-invaginations of the plasma membrane.

Vesiculovacuolar organelle

(VVO). Transendothelial channel created by fusion of vesicles, for example, in response to VEGF.

Cardinal vein

An important drainage vessel for deoxygenated blood in the embryo.

Mesenchymal cell

Embryonic connective (supporting)-tissue cell.

Neovascularization

Formation of new blood vessels, often in conjunction with disease processes.

Age-related macular degeneration

(AMD). Degeneration of the cells of the macula (part of the retina) in the eye and neovascularization in the choroids, which results in blurred vision and can cause blindness. Leading cause of blindness among the elderly in the western world.

Fenestrated capillaries

Small, permeable blood vessels with circular pores, covered with a thin diaphragm.

Tip cell

The endothelial cell that heads a blood-vessel sprout during angiogenesis.

Pericytes

Cells that surround small blood vessels, particularly numerous around post-capillary venules.

Collapsin/semaphorin

Transmembrane or secreted molecules that guide the path of growing nerve axons.

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Olsson, AK., Dimberg, A., Kreuger, J. et al. VEGF receptor signalling ? in control of vascular function. Nat Rev Mol Cell Biol 7, 359–371 (2006). https://doi.org/10.1038/nrm1911

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