Cardiovascular disease and arteriogenesis

Cardiovascular disease (CVD) is the single largest cause of death in the UK.  It accounts for around 200,000 deaths a year, mostly as a result of heart disease or a stroke.

Arterial blockage (or occlusion) is a major factor in CVD.  Blockage may occur when a blood clot obstructs the flow of blood in an artery.

Collateral vessel formation

After an arterial blockage, collateral vessels can develop by a process called arteriogenesis, which improves blood supply to the area.  Arteriogenesis remodels existing blood vessels rather than building new ones (new vessels are formed by a different process called angiogenesis).
The collateral vessels around the blockage might be extremely tiny and carry almost no blood normally.  However, due to the nearby blockage, there is increased pressure on the surrounding collateral vessels. This pressure stimulates the process of arteriogenesis, which enlarges the diameter of the vessels, allowing increased blood flow though them.

You might like to imagine the collateral vessels as minor roads around a motorway.  When the motorway is open it carries most of the traffic. However, if there is an accident and the motorway becomes blocked, a diversion is set up and the surrounding roads are used to drive around the accident.  If the motorway is permenantly shut, in order to make sure the other roads are able to cope with the increased amount of traffic, they might be widened (although in reality that might take a lot longer then arteriogenesis!

Using fish

Studying arteriogenesis in mammals is difficult because:

• Visualising arteries is technically challenging.
• It is time-consuming to remove single genes to study their effect.
• When an artery is blocked, lack of oxygen (hypoxia) induces processes unrelated to arteriogenesis.

• Their transparency makes visualisation of vessels easy.  We have a GFP line where all the vasculature is labelled, which means we can examine vessel formation, growth and remodeling in great detail in live fish.
• We're able to easily manipulate the genes we're interested in, and examine the effects on arteriogenesis.
• Zebrafish do not suffer hypoxia after arterial blockage.  Hypoxia is a decrease in oxygen supply, luckily the fish embryos are so small, oxygen can diffuse into them from the water.

The aims

Arteriogenesis has the potential to improve the consequences of arterial blockage.  However, only a third of patients develop collateral vessels and many factors such as age and diabetes impair arteriogenesis.

Very little is known about the genetic and cellular regulation of arteriogenesis, in part due to the technical challenges of studying this in mammals. We hope that increasing our understanding of arteriogenesis using zebrafish may ultimately lead to the generation of new therapies for patients with with occluded arteries.

Humans can be born with a narrowing or blockage of the artery leading from the heart (coarctation of the aorta).

The zebrafish aorta runs down the centre of the trunk (upper panel). Reducing expression of a gene called PTHR1 causes an blockage of the aorta similar to human aortic coarctation (lower panel).

We recently identified a drug that corrects this defect.