Understanding how the body maintains the balance between blood vessel formation and stabilisation could help treat blood vessel disorders, cancer and prevalent eye diseases.
Blood vessels in the retina in healthy mice (left) compared to mice lacking a gene in a key signalling pathway, the Bmp9 pathway (right) The structure of the vessels appears disorganised in the mice with the mutation. Credit: Tommaso Ristori, Developmental Cell.
Blood flows around the body through a complex network of vessels, which must constantly adapt to changing needs. The balance between growing new vessels and stabilising existing vessels, so they aren’t leaky, must be finely tuned.
Abnormal blood vessel growth has been linked to a wide range of diseases, including bleeding disorders, cancer and diabetic retinopathy, but the underlying mechanisms aren’t fully understood.
Computational biologist Katie Bentley uses modelling to simulate processes in the body, aiming to work out how and when blood vessels decide to branch or stabilise. A few years ago, she became interested in how these branching decisions affect a genetic disorder, hereditary haemorrhagic telangiectasia (HHT), which affects approximately 1 in 5000 people.
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“In HHT, blood vessels grow in a disordered way, leading to frequent bleeding from the skin and nose, and sometimes serious complications affecting major organs, including the brain,” Katie explains. “It’s currently incurable, but we think we may have found a new target for potential treatment.”
Katie and her team have focused on pathways of chemical signals that coordinate blood vessel branching. Working with Bruno Larrivée at the University of Montréal, they explored the interaction between the Bmp pathway, which is involved in shaping developing vessels and guiding how quickly vessel cells multiply, and the Notch pathway, which enables direct communication between neighbouring vessel cells and determines where and when new branches should form when a tissue needs more blood vessels. The Bmp pathway contains the gene mutated in HHT.
“Bruno’s first studies indicated that these two pathways act independently. With no crosstalk between them, their effects should just add up,” says Katie. “But something bothered us for years: in experiments, when both pathways were switched on, the effect was three times as strong. This suggested to us that there was a ‘middleman’ coordinating the two pathways and boosting their combined effect.”
In new research published today in Developmental Cell, the team used computer modelling to test how and where the two pathways interacted, on the hunt for this mysterious amplifying protein.
“The simulations revealed that an enzyme called Lunatic fringe, which has previously been linked to blood vessel formation, was the missing link between these two pathways," says first author Tommaso Ristori, previously at the Crick and now at the Eindhoven University of Technology. “Further computer models confirmed that Lunatic fringe boosts the Notch pathway when Bmp9 signalling is switched on.”
Katie added, “We also showed this in living cells, from mice, zebrafish and humans. Now we strongly suspect that Lunatic fringe might underpin some of the effects on blood vessels we see in HHT – this wouldn't have been possible without integrating computer simulations with experiments.”
Blood vessels in the retina in healthy mice (left) compared to mice lacking a gene in a key signalling pathway, the Bmp9 pathway (right). Lunatic fringe is seen in the stronger vessel branches in the bottom left image, absent in the bottom right. Credit: Tommaso Ristori, Developmental Cell.
Katie and team then focused on what Lunatic fringe was doing during blood vessel branching. “Blood vessel branching decisions are mediated by Notch signalling, but slowed down by the Bmp9 pathway,” Katie explains. “This complicated process affects the overall structure of the blood vessel network: slower decisions can lead to sparser branches.”
The researchers found that Lunatic fringe was a key player in this process, as inhibiting Lunatic fringe resulted in more branching.
“We think it’s a clever way to get the balance right,” says Bruno. “We need networks to branch, but also stay stable to avoid leakiness, and Bmp9 in the blood boosts the amount of Lunatic fringe to maintain the balance between the pathways.”
Notch signalling is also required to stop blood vessels forming tangles called arteriovenous malformations, which are associated with abnormal bleeding in HHT.
And when Katie and team modelled the effect of boosting Lunatic fringe in cells with HHT-associated mutations, they saw a rise in Notch signalling (in vessel-forming endothelial cells and their supporting cells) required for better organisation of the vessels. These findings suggested that boosting this missing link could restore some of the balance maintained by the two pathways.
“Targeting Notch signalling itself is risky as it has so many critical functions throughout the body,” says Katie. “But amplifying Lunatic fringe could be a smart way to restore the status quo without disrupting other functions.”
Beyond HHT, the team believe that boosting Lunatic fringe holds potential for other diseases. “As well as targeting blood vessel malfunctions in cancer or certain eye diseases, this breakthrough could help scientists grow blood vessels in tissues engineered in the lab or for regenerative medicine,” adds Tommaso. “I see this as just the start of very exciting research in the field.”
