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Europe PMC team

 | 21 May 2014


A divorce in development: single regulators can raise arteries alone

Image Source: Serial/Trash
how blood vessels are born and propagated is vital for the treatment of a whole
host of diseases including heart disorders, diabetes and cancer. Scientists
from Oxford’s Ludwig Institute for Cancer Research have begun to reveal the mechanism
by which the switching on of specific genes leads to the development of

vast network of blood-carrying arteries feeds our body with the oxygen and
nutrients it needs to survive. Within a young embryo, this network takes its
primitive shape in a series of stages. First, the cell type which will later make
up the inner-walls of all blood vessels, the endothelial cells, is generated. Then
simple tube-like structures of these endothelial cells must differentiate into
either arteries or veins.

the story doesn’t end there – the process of sprouting new blood vessels
continues throughout life and indeed maintaining just the
right distribution is critical to our health. Too few, too many or abnormally-developed
blood vessels can all lead to disease. Interestingly, although cancer and
Alzheimer’s disease are very different conditions, scientists believe that the
underlying molecular processes responsible for the defective blood vessel
development that comes with them are very similar and therefore exciting
targets for research.

aspects of our development, from the formation of vital organs within the
embryo to the healing of wounds in adulthood, utilise similar molecular tools
to lay down the pattern which governs how cells and tissues specialise into one
of many types – rather like a blueprint. External signalling molecules are
deployed to pass instructions to cells depending on where they lie in the
overall blueprint. These signals can be sensed by each cell individually via
receptor molecules protruding from their surface.

are confident of the signalling molecules released during artery development. Vascular
Endothelial Growth Factor (VEGF) spreads
diffusely across tissues and is the primary driver of general blood vessel
formation. The Notch pathway, which operates when adjacent cells touch, is
implicated in deciding which vessels become arteries. However, signalling
messages are short lived – how does an artery know to remain an artery? It is
this last link in the chain that until now scientists have been most unsure
about – how can several signalling pathways be combined inside the cell so that
the correct genes are turned on for operating an artery?

cells carry a copy of the entire genome, but few genes are required in every
cell or all the time. Genes lie adjacent to ‘enhancers’, DNA sequence elements that
do not encode protein but rather allow control of when, where and how fast a
gene is read. Such control is governed by DNA-binding proteins, which sit on
the DNA structure and interact with the gene-reading machinery.

Image Source: Shutterstock Copyright: Crystal Eye Studio

Sarah De Val and her colleagues at Oxford have conducted a series of
experiments in mice and zebrafish that reveal which DNA-binding proteins are
important in the formation of arteries. They first pinpointed which enhancers are
most important for the activation of an artery-specific Notch gene before
demonstrating which of the known DNA-binding proteins engage them. These
included a DNA-binding component of the Notch pathway and three members of the
SOX-gene family, utilised during development throughout the animal kingdom.

fusing copies of the artery enhancers to a bacterial gene that produces a bright
blue protein when activated, it was possible for the researchers to trace the pattern
of artery formation at different stages during embryo development. Unsurprisingly,
when they cut out the binding sites at which the proteins responsible for
formation of endothelial cells associate with enhancer DNA, or chemically
disabled the VEGF signalling pathway, the normal pattern of Notch gene
activation was completely lost. But
intriguingly, deleting the binding sites for the SOX and Notch proteins
only had a severe effect when carried out in parallel – loss of regulation by
either SOX or Notch individually was of little importance.

finding was echoed by injecting inhibitory DNA molecules into embryos to
simultaneously turn off the genes encoding the DNA-binding SOX and Notch
proteins. Although endothelial cells were able to form a network of primitive
blood vessels, the principle artery, the aorta, was missing and none of the known
genes common to arteries were activated.

a general rule, developmental characteristics tend to emerge in cells located
in regions where two or more necessary signals overlap. This research, proclaiming
that proteins of either the SOX or Notch pathways alone are sufficient for much
of artery function without the other,
intriguingly contradicts this.

Highlighting the fact that the vascular system is extremely
sensitive to genetic fine-tuning, Dr De Val’s study reveals some of the first molecular
targets for potential vascular disease therapies. At the same time, it exposes some
unusual molecular intricacies that will continue to excite scientists for some

This summary by Christopher Waite was shortlisted for Access to Understanding 2014 and was commended by the judges. It describes research published in the following article, selected for inclusion in the competition by the British Heart Foundation:

PMCID: PMC3718163
N. Sacilotto, R. Monteiro, M. Fritzsche, P.W. Becker, L. Sanchez-del-Campo, K. Liu, P. Pinheiro, I. Ratnayaka, B. Davies, C.R. Goding, R. Patient, G. Bou-Charios & S. De Val.
Proceedings of the National Academy of Science USA (2013) 110(29), 11893-11898.

Access to Understanding entrants are asked to write a plain English summary of a research article. For Access to Understanding 2014 there were 10 articles to choose from, selected by the Europe PMC fundersThe articles are all available from Europe PMC, are free to read and download, and were supported by one or more of the Europe PMC funders.

Look out here and on Twitter @EuropePMC_news for further competition news and other Europe PMC announcements.    

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