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T

he vascular system is the supply network of the human

organism and delivers oxygen and nutrients to every area

in the body. A functional vasculature is of key importance

for healthy people, but it also plays an important role in many

diseases – in wound healing and, most notably, in cancer.

Tumours can only grow if they connect to the vasculature network,

and they do so by attracting sprouts from existing vascular fields

and allowing them to form a tumour vasculature so that the

rapidly growing cancer cells can be nourished and provided with

oxygen. A better understanding of blood vessel formation and

remodelling in health and disease would help to devise better

treatment for a number of diseases and is the focus of much

research, both in basic and in applied science.

Whilst much has been learnt from studies in many different model

systems as well as in cultured cells, the behaviour of endothelial

cells in their native environment has been more difficult to

document due to the lack of model systems allowing for deep,

long term imaging at high temporal and spatial resolution. In the

past decade, the zebrafish embryo has helped to visualise cell

behaviour in the developing vasculature due to the transparence

and external development of the embryo.

The expression of green fluorescent protein fusion proteins

labelling distinct compartments of endothelial cells and the

subsequent imaging of the developing vasculature using high

temporal and spatial resolution confocal imaging in zebrafish

embryos have allowed following endothelial cells as they build up

complex vascular networks. It turns out that these cells are

incredibly dynamic, dividing and rearranging rapidly as they form

sprouts and establishing connections to form new vascular loops.

Luminal space

Of major importance is the formation of an interconnected

luminal space which eventually allows blood cells to circulate

throughout the vascular tubes. Several cellular models have now

been described which lead to the co-ordinated formation of

sprouts, their connection and subsequent lumen formation in the

newly established vascular loops. These studies can now be

complemented with molecular analysis, with the ultimate aim of

providing cellular and molecular pathways used in health and

possibly disrupted in disease. Such molecular pathways might

allow the better manipulation of vessel formation in disease, by

either blocking sprouting or increasing it.

So far, research on the vascular system has primarily focused on

the formation of vascular networks during development. Our

research group at the Biozentrum of the University of Basel has

now investigated how blood vessels are removed (pruned) in the

zebrafish and we have discovered that the cells have the ability to

self-fuse at the membrane margins. It was previously unknown that

endothelial cells of blood vessels of vertebrates have this property.

Architectural plan

The formation of blood vessels follows a complicated architectural

plan. At first glance, cell behaviour during vascular regression

seems to be similar but reversed from the behaviour during the

outgrowth and connection of new vessels, but it must differ at the

molecular level. During vascular regression, most of the cells

consecutively migrate and incorporate into the neighbouring

functional vessels and are reused as building blocks in these

vessels. The last single cell that remains in the pruning vessel

reaches around the lumen and the membrane margins of this cell

undergo fusion, thereby closing the vessel and ensuring its

tightness. This process, called cell self-fusion, ensures a controlled

closure of a regressive blood vessel, thus preventing blood

leakage. For the first time, the process of self-fusion of cells has

been observed in vertebrates. Such cell behaviour was previously

only known in simpler organisms such as nematodes.

During the development of the vascular network, blood vessels are

constantly formed, but many of them are only required temporarily

and blood flow becomes inefficient as new vessels are added or

new connections are made. Just like a disused arm of a highly

branched river, the flow of fresh blood through these vessels is

interrupted and the organism begins to prune this side arm.

Research at the Biozentrum of the University of Basel aims to understand the

formation and remodelling of blood vessels at the cellular level

Understanding blood vessels

152

I S S U E S E V E N

H O R I Z O N 2 0 2 0 P R O J E C T S : P O R TA L

www.horizon2020projects.com

P R O F I L E

C A N C E R & C A R D I O V A S C U L A R D I S E A S E

Fig. 1 Endothelial cells in a living zebrafish embryo head. Blood vessels

are shown in red, nuclei of endothelial cells in green