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Arteries and veins: making a difference with zebrafish

Key Points

  • One of the most fundamental distinctions between blood vessels is that between arteries and veins. These two types of vessel are structurally different and have long been functionally defined by the direction of the flow of blood that they carry. Recent work indicates that the endothelial cells that line the lumens of these two vessel types have distinct molecular identities.

  • Arterial–venous endothelial-cell identity is determined during embryogenesis, before circulation begins. Recent work in several vertebrates has begun to define the molecular pathways that specify this differentiated fate. The zebrafish has been particularly useful for in vivo dissection of the signalling pathways that regulate arterial and venous fate.

  • Zebrafish provide several advantages for studying vascular development. They are amenable to large-scale forward genetics analysis. The optical clarity, external embryonic development and small size of zebrafish embryos also allow easy visualization of the vasculature and allow screening for vascular-specific mutants.

  • Components of the Notch pathway are expressed in the blood vessels of many vertebrates, and several Notch receptors are expressed specifically in arterial endothelial cells. Studies in zebrafish have now shown that the activation of Notch signalling in endothelial cells promotes arterial cell fate and represses venous differentiation.

  • Studies in the zebrafish have also shown that the well-known signalling molecules — sonic hedgehog and vascular endothelial growth factor (Vegf) — act upstream of Notch signalling to promote arterial differentiation of endothelial cells. Several recent studies in the mouse have confirmed that Vegf also has an important role in arterial specification in this organism.

  • The powerful genetic tools provided by the zebrafish will allow both the identification of other molecules that are involved in arterial differentiation and the placement of these molecules in a genetic pathway. The conservation of signalling mechanisms and the similarity of embryonic and adult neovascularization indicate that the differentiation of arterial and venous endothelial cells will probably be relevant in the context of human disease.

Abstract

Arteries and veins are structurally different and have long been functionally defined by the direction of blood flow that they carry. However, a growing body of evidence indicates that the identity of the endothelial cells that line these vessels is determined in the developing embryo, before circulation begins. Recent work on the zebrafish has led to the identification of signals that are responsible for arterial and venous differentiation of endothelial cells, and highlights the unique benefits of this model organism in the study of vascular development.

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Figure 1: Molecular markers define arterial and venous cell identity.
Figure 2: The zebrafish vasculature.
Figure 3: Genetic analysis of signalling pathways.
Figure 4: A model for arterial differentiation in zebrafish.

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Author information

Affiliations

Authors

Corresponding author

Correspondence to Brant M. Weinstein.

Related links

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DATABASES

ArkDB

NRP1

LocusLink

Acvrl1

Dll4

Efnb2

Ephb2

Ephb4

Notch

Notch1

Notch2

Notch4

Shh

Su(H)

OMIM

haemorrhagic telangiectasia type II

ZFIN

deltaC

efnb2a

ephB4a

fli1

flt4

grl

mib

notch5

syu

tbx20

FURTHER INFORMATION

Dawid lab in situ screen

Interactive Atlas of Zebrafish Vascular Anatomy home page

Thisse lab in situ screen

Weinstein lab

Glossary

LATERAL MESODERM

Consists of mesodermal cells that, after gastrulation, lie between the ectodermal and endodermal layers in vertebrate embryos. These cells give rise to haematopoietic, vascular and kidney tissue.

VASCULOGENESIS

De novo formation of blood vessels through the coalescence of endothelial cells. It often involves extensive migration of endothelial cells from their point of origin to the site of vessel formation.

ANGIOGENESIS

The formation of new blood vessels from pre-existing ones. It is often associated with cell division and the subsequent sprouting of the endothelial cells that contribute to the growing blood vessel.

YOLK SAC

In mouse, the extra-embryonic tissue that surrounds the yolk.

ANGIOBLAST

An undifferentiated endothelial progenitor cell that has yet to integrate into a blood vessel.

MIDLINE

The notochord and its anterior extension, the prechordal plate.

ARTERIOVENOUS MALFORMATION

An abnormal connection between a main artery and vein, such as the dorsal aorta and posterior cardinal vein, that leads to a circulatory bypass.

MORPHOLINO

A chemically modified antisense oligonucleotide that can specifically inhibit translation of a target mRNA.

NOTOCHORD

A transient structure that is located at the midline in the trunk of developing vertebrate embryos.

NEURAL TUBE

Presumptive spinal cord.

SOMITES

The segmental blocks of mesenchyme that are adjacent to the notochord and that give rise to the muscle tissue of the trunk.

ARTERIOLE

A small-calibre artery that is continuous with a capillary network and that is associated with only one or two layers of surrounding smooth muscle cells.

VENULE

A small-calibre vein that is continuous with a capillary network.

LASER SCANNING CONFOCAL MICROSCOPE

A light microscope that allows imaging of fluorescent structures in thick (tens to hundreds of micrometres) specimens. A series of optical 'slices' are collected using a scanning laser beam and specially designed optics to eliminate out-of-focus excited fluorescence. The slices are reconstructed to provide detailed 3D representations of the image data.

TELANGIECTASIA

A dilation of the small vessels in capillary beds that often leads to hyperpermeability and haemorrhage.

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Lawson, N., Weinstein, B. Arteries and veins: making a difference with zebrafish. Nat Rev Genet 3, 674–682 (2002). https://doi.org/10.1038/nrg888

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