Europe PMC Team

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[Understanding  
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  
arteries.]{style="font-family: \"arial\" , sans-serif; line-height: 150%;"}[ ]{style="font-family: \"arial\" , sans-serif; line-height: 150%;"}
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[A  
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.
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[But  
the story doesn't end there -- the process of sprouting new blood
vessels  
continues throughout life and indeed maintaining just[
]{style="color: red;"}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.]{style="font-family: \"arial\" , \"sans-serif\";"}
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[All  
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.]{style="font-family: \"arial\" , \"sans-serif\";"}
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[Scientists  
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?]{style="font-family: \"arial\" , \"sans-serif\";"}
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[All  
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.]{style="font-family: \"arial\" , \"sans-serif\";"}

  
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[Dr  
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.]{style="font-family: \"arial\" , sans-serif; line-height: 150%;"}
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[By  
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.
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[This  
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.
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[As  
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.]{style="font-family: \"arial\" , \"sans-serif\";"}  
[  
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[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  
time.]{style="font-family: \"arial\" , sans-serif; line-height: 150%;"}
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*[  
]{style="font-family: \"arial\";"}*  
*[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
articl]{style="font-family: \"arial\";"}[e, ]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}*[*selected
for inclusion in the competition by the British Heart
Foundation*]{style="background-color: white; color: #5a595e; font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif; line-height: 20px;"}*:*
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[[Analysis
of ]{style="font-family: \"arial\" , sans-serif; line-height: 14px;"}*DII4*[ regulation
reveals a combinatorial role for Sox and Notch in arterial
development]{style="font-family: \"arial\" , sans-serif; line-height: 14px;"}](http://europepmc.org/articles/PMC3718163){target="_blank"
rel="noopener"}
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[PMCID: PMC3718163]{style="font-family: \"arial\" , sans-serif;"}
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[[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.]{style="font-size: xx-small;"}]{style="font-family: \"arial\" , sans-serif;"}
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[[*Proceedings of the National Academy of Science USA* (2013) 110(29),
11893-11898.]{style="font-size: xx-small;"}]{style="font-family: \"arial\" , sans-serif;"}
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[*[Access to
Understanding](http://europepmc.org/sciencewritingcompetition){target="_blank"
rel="noopener"}* 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
funders](http://europepmc.org/Funders/){target="_blank"
rel="noopener"}. **The 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.**]{style="font-family: \"arial\" , sans-serif; line-height: 24px;"}

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[Image Source: Serial/Trash]{style=“font-family: "arial" , sans-serif; line-height: 150%;”}  [Understanding how blood vessels are born and propagated is vital for the treatment of a whole host of diseases including heart disorders, diabetes and cancer.

Messaggi di Rogue Scholar

A divorce in development: single regulators can raise arteries alone