Key Points
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New blood vessel morphogenesis by angiogenic sprouting requires the highly coordinated and dynamic control of endothelial cell (EC) behaviour. Recent studies shed new light on the complex molecular mechanisms controlling EC behaviour in sprouting vessels, providing important insights into key biological processes, such as branching morphogenesis, tubulogenesis and mechanotransduction.
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Angiogenic branching involves the hierarchical sprouting of leading endothelial 'tip cells' (TCs) and trailing 'stalk cells' (SCs). Signalling via vascular endothelial growth factor receptor 2 (VEGFR2) and VEGFR3 promotes TC behaviour, whereas expression of the decoy receptor, VEGFR1, limits TC formation.
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Activation of Notch signalling in SCs negatively regulates VEGFR function to repress TC behaviour and maintain the hierarchical organization of sprouting TCs and SCs. Consequently, the cell-type-specific transcriptional control of Notch ligand expression or the post-translational control of Notch activity act as key control points that determine TC and SC fate.
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Vascular tubulogenesis is an essential aspect of angiogenic sprouting that generates a blood vessel lumen capable of carrying blood flow. Emerging evidence indicates that vascular lumen formation is a multistep process that is initiated by the acquisition of EC apicobasal polarity and is regulated by cell–matrix interactions, as well as partitioning defective 3 (PAR3) and VEGFR signalling.
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Increasing evidence shows that multiple signalling pathways have common roles in the guidance of both migrating axonal growth cones and ECs. In particular, signalling mediated by the neuronal guidance cues uncoordinated 5 homologue B (UNC5B), Roundabout homologue 4 (ROBO4), plexin D1, neuropilins, ephrin B2 and ephrin receptor B4 (EPHB4) has key roles in vascular development.
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Post-transcriptional control of blood vessel formation by microRNAs is involved in the fine-tuning of pro-angiogenic signalling during development, disease and in response to mechanical cues, such as blood flow. Furthermore, recent studies identify important post-translational mechanisms that control VEGFR membrane trafficking and signalling during angiogenesis in vivo.
Abstract
The vertebrate vasculature forms an extensive branched network of blood vessels that supplies tissues with nutrients and oxygen. During vascular development, coordinated control of endothelial cell behaviour at the levels of cell migration, proliferation, polarity, differentiation and cell–cell communication is critical for functional blood vessel morphogenesis. Recent data uncover elaborate transcriptional, post-transcriptional and post-translational mechanisms that fine-tune key signalling pathways (such as the vascular endothelial growth factor and Notch pathways) to control endothelial cell behaviour during blood vessel sprouting (angiogenesis). These emerging frameworks controlling angiogenesis provide unique insights into fundamental biological processes common to other systems, such as tissue branching morphogenesis, mechanotransduction and tubulogenesis.
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Acknowledgements
We apologize to those authors whose work could not be referenced directly because of space limitations. S.P.H. is a Wellcome Trust research career development fellow. Vascular work in the laboratory of D.Y.R.S. is supported in part by grants from the US National Institutes of Health (HL54737) and the Packard Foundation to D.Y.R.S.
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Glossary
- Ischaemic diseases
-
Disease states that are characterized by a restriction in the blood supply to an organ or tissue, such as ischaemic heart disease, stroke or ischaemic colitis.
- Metastasis
-
The spread of cancer cells from the site of a primary tumour to distant parts of the body.
- Basement membrane
-
The sheet-like layer of laminin- and collagen-rich fibres that separates endothelial or epithelial cells from adjacent tissues.
- Filopodial extensions
-
Thin cytoplasmic protrusions containing bundled actin filaments that dynamically extend from the leading edge of migrating cells and explore the surrounding microenvironment.
- Neuronal growth cones
-
Specialized guidance structures located at the distal end of developing axons that sense extrinsic guidance cues to direct the movement of axons.
- Vascular lumen
-
The open and unobstructed (or patent) space within a hollow vascular tube that is lined by endothelial cells and through which blood flows.
- Anastomosis
-
The union of two hollow structures so as to interconnect and establish continuity between both structures.
- Abluminal surface
-
The surface away from the lumen (to distinguish it from the luminal surface, which is the one adjacent to the lumen).
- Intussusceptive angiogenesis
-
Blood vessel formation by the splitting of existing vessels. Intussusception involves the insertion of a tissue pillar into the vascular lumen to split a single parent vessel into two daughter vessels.
- Hypoxia
-
A deficiency in the supply of oxygen to an organ or tissue.
- Haploinsufficient
-
The term applied to a gene of a diploid organism if a single copy of that gene is insufficient to support a wild-type phenotype.
- Heparan sulphate
-
A linear polysaccharide present on the surface of cells or in extracellular matrices, which function by binding wide varieties of proteins (such as growth factors) to regulate key biological processes.
- Decoy receptor
-
Generally considered to be a non-signalling receptor that binds a ligand and reduces the interaction of the bound ligand with its signalling receptor.
- Lymphangiogenesis
-
The formation of new lymphatic vessels by sprouting from pre-existing vessels.
- Lateral inhibition
-
In developmental biology, this term refers to the ability of a cell to inhibit the differentiation of its immediate neighbours through cell–cell interactions.
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Herbert, S., Stainier, D. Molecular control of endothelial cell behaviour during blood vessel morphogenesis. Nat Rev Mol Cell Biol 12, 551–564 (2011). https://doi.org/10.1038/nrm3176
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DOI: https://doi.org/10.1038/nrm3176
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