Researchers have identified two proteins that play an essential role in the formation of new blood vessels. The proteins are part of the Hippo signaling pathway, which regulates organ growth and size. “Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue’s metabolic milieu and often occurs at nutrient-deficient sites,” explained the researchers in the paper. “However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown.”
Blood vessels are essential for providing nutrients to all body tissues, and if those blood vessels stop working properly it can lead to the development of diseases. Age-related cardiovascular conditions can cause blood vessels to atrophy, while cancerous tumors often involve excessive growth of misrouted blood vessels. In order to develop targeted therapies for patients, it is important to understand how the growth of new blood vessels is regulated in the body.
The researchers found that these processes were instructed by Yes-associated protein 1 (YAP)/WW domain-containing transcription regulator 1 (WWTR1/TAZ)-transcriptional enhanced associate domain (TEAD), which is a transcriptional module whose function is highly responsive to changes in the tissue environment. In a mouse model, they determined that ECs that lack YAP/TAZ, or their transcriptional partners TEAD1, 2 and 4, failed to divide, which resulted in stunted vascular growth in mice. When there was activation of TAZ, there was a proliferation of new blood vessel formation, leading to vascular hyperplasia.
“By sensing and responding to mechanical, metabolic, and soluble signals, these proteins coordinate tissue growth responses,” explained the researchers. When YAP and TAZ are active in the cells of the endothelium, they read genes which leads to the increased growth of certain surface transporters, which allows the cells to absorb more nutrients that are necessary for growth and cell division. The increased absorption triggers the activation of another protein, mTOR, which is a control point in cells that trigger growth and cell division, which allows new blood vessel networks to expand.
The researchers have not established what signals regulate YAP and TAZ activity in endothelial cells, must have identified a mechanism that allows blood vessels to align growth with their surroundings, which prevents endothelial cells from dividing if the metabolic resources to support that process are not there. The researchers are now studying the extent to which this mechanism is involved in regeneration and repair processes, which rely heavily on blood vessels, and whether malfunctions in the hippo signaling pathway can cause vascular disease in humans.
You can read more about the study in the paper – A YAP/TAZ-TEAD signalling module links endothelial nutrient acquisition to angiogenic growth – which was recently published in Nature Metabolism. DOI: 10.1038/s42255-022-00584-y