What causes blood vessels to grow?

Joint press release of the Max Delbrück Center for Molecular Medicine and the Berlin Institute of Health in Charité

Blood vessels run through the human body and ensure that our organs receive all the nutrients and oxygen they need. If these fine-grained networks stop working as they should, we run the risk of developing disease. While age-related cardiovascular disease often leads to atrophy of blood vessels, malignant tumors are characterized by overgrowth of misrouted blood vessels. Wet macular degeneration is also associated with the sprouting of new blood vessels in the wrong place. In the worst cases, the condition can cause blindness.

A door opener for nutrients

“To help us develop targeted therapies for these kinds of diseases, we want to know exactly how the growth of new blood vessels — a process called angiogenesis — is regulated in the body,” said Potente, a professor of translational vascular biomedicine at the University of Groningen. Berlin Institute of Health in Charité (BIH) and a visiting researcher at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). His Angiogenesis & Metabolism Laboratory is part of the Berlin Center for Translational Vascular Biomedicine, an interdisciplinary facility that is a joint focus of the BIH, Charité – Universitätsmedizin Berlin and the MDC.

Potente and his international team have now made some important advances: In Nature Metabolism, the researchers write that two proteins called YAP and TAZ play a crucial role in germinating blood vessels, even under challenging metabolic conditions. The proteins are part of the Hippo signaling pathway, which regulates organ growth and size in almost all living things. “When these two molecules are active in the cells of the inner wall of the blood vessels – the endothelium – they read genes that lead to an increased growth of certain surface transporters,” says Potente. “This allows the vascular cells to absorb more nutrients that are important for growth and cell division.” YAP and TAZ, which both function in a similar way, therefore act as a kind of door opener.

“This increased nutrient absorption leads to the activation of another protein called mTOR,” says Potente. mTOR is an important control point in cells that initiates growth and cell division. “This allows new blood vessel networks to expand,” he explains. However, the team does not yet know which signals regulate the activity of YAP and TAZ in endothelial cells.

Mouse retinas insights

The study’s lead author is Dr. Yu Ting Ong of the Max Planck Institute for Heart and Lung Research in Bad Nauheim in western Germany. Before moving to Berlin, Potente ran a laboratory there. Also involved in the report was Professor Holger Gerhardt, head of the MDC’s Integrative Vascular Biology Laboratory, who works alongside Potente in the Käthe Beutler building in Berlin-Buch. “Together we have discovered a mechanism by which blood vessels can closely tailor their growth to the situation in their environment,” says Gerhardt. “The mechanism stops endothelial cell division if the metabolic resources necessary for the process are not there.”

The findings are based on mouse experiments. The mouse retina is an ideal model for studying the development of blood vessels. “Using genetically modified mouse lines, we showed how endothelial cells that do not produce YAP and TAZ almost never divide,” says Potente. “This inhibited vessel growth in the mice.” Especially the TAZ protein plays an important role in this process, while YAP is the determinant in most other cell types.

Important molecular machinery

“Since new blood vessels are often formed in tissues with poor blood supply, endothelial cells must be able to grow in the most challenging metabolic conditions,” says Potente. “That’s why it’s so important that these cells have molecular machinery that recognizes and responds to subtle changes in the extracellular environment.”

Together with their teams, Potente and Gerhardt now want to investigate to what extent the mechanism – which they described during tissue development – is also involved in regeneration and repair processes that are highly dependent on blood vessels. “We are particularly interested in investigating whether and, if relevant, how disturbances in that signaling pathway can lead to vascular disease in humans,” says Potente.

More information

Berlin Center for Translational Vascular Biomedicine

Michael Potente Laboratory

Holger Gerhardt Laboratory

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