Self-reinforcing endothelial signalling drives venous malformation growth
In a new study from IGP, researchers have discovered a molecular signalling loop that drives the progressive growth of venous malformations. The results suggest that targeting the key proteins within this loop may offer new therapeutic options.
Dermal vasculature in the ear skin from a mouse model of Pik3ca-driven venous malformation, showing vascular lesions in veins and venous capillaries (grey), covered by smooth muscle cells (blue). Image by Marle Kraft.
Venous malformations (VMs) are a chronic disease of the blood vasculature that varies from superficial, asymptomatic blue or purplish marks to potentially life-threatening lesions. The malformations may develop in various tissues, but are most common in or under the skin. They are caused by mutations in the endothelial cells that line the inside of blood vessels, which activate a specific signalling pathway that leads to abnormal growth of veins.
There is no curative treatment but drugs that inhibit the overactivated signalling pathway are currently used in the clinic to relieve symptoms. To improve or develop new therapies, there is a need for increased knowledge about the mechanisms behind how the malformations are formed. In the current study, the researchers have mapped in detail the signalling processes that drive the disease.
“Mutations in the gene PIK3CA, which encodes a key signalling molecule, are known to drive venous malformation development. We could confirm that these mutations directly promote the growth of mutant endothelial cells in mice. In addition, we found that PIK3CA mutations boost the activity of the endothelial cell surface receptor TIE2, which functions upstream in the signalling pathway. These changes create a self-reinforcing loop that amplifies the signalling and drives vascular lesion growth,” says Taija Mäkinen, who led the study.
Unfortunately, currently used treatments are often ineffective in advanced disease stages. Here, the new results are important since the researchers could show that breaking the signalling loop could significantly reduce the growth of advanced lesions in mice expressing mutant PIK3CA. In addition, existing treatment can have significant side effects, as they can disrupt critical signalling processes in essentially all cell types.
“Given that the TIE2 signalling pathway primarily affects the endothelial cells, an important finding from our study is that targeting this pathway may offer a more specific and thus safer and effective therapeutic option for patients with advanced venous malformations, compared to targeting PIK3CA, which is broadly expressed,” says Taija Mäkinen.
The study was a collaboration with researchers in Germany, Portugal, Spain and Belgium. It has been published in the journal Nature Cardiovascular Research.