The Yes protein controls leakage from blood vessel to surrounding tissues

2022-12-19

Researchers at IGP have identified a protein involved in regulating leakage from blood vessel. Its role in controlling cell–cell contacts, challenges prior knowledge and opens up new avenues for future therapeutic development in diseases involving vessel leakage and tissue swelling.

The lining of the body’s blood vessels is made up of endothelial cells. They are connected to each other and create a barrier that controls what is released of from the vessels to the surrounding tissues. If this control is malfunctioning, which can happen in diseases such as cancer, eye diseases and chronic inflammation, cells and molecules can leak out. This causes accumulation of fluids in the tissues, edema, which can contribute to the complication of the diseases.

In the current study, the researchers found that the protein Yes has a principal role in regulating the contacts between endothelial cells and thus in controlling vessel leakage.

“The molecule VE-cadherin is located on the endothelial cell surface where it connects the cells to each other. We found that when the Yes protein is active it modifies the VE-cadherin molecules so that cells bind less tight to each other. This leads to an increased leakage from the vessels,” says Yi Jin, researcher at IGP and first author of the study.

Yes modifies VE-cadherin by phosphate attachment, a process called phosphorylation. By studying genetically modified mice, the researchers could manipulate the levels of Yes in the endothelial cells to see how it affected both the phosphorylation of VE-cadherin and vessel leakage.

“In mice where Yes was missing, we saw almost no phosphorylated VE-cadherin but unexpectedly, they still exhibited increased vascular leakage. In mice with higher levels of Yes we found increased levels of phosphorylated VE-cadherin but it did not affect vascular leakage. This shows that the long-held notion that VE-cadherin phosphorylation is a prerequisite for vascular leakage is not true,” says Lena Claesson-Welsh, who led the study.

The protein Src is related to Yes and it can also phosphorylate VE-cadherin. It has also been implicated in regulating vessel leakage. When the researchers compared the effect of Yes and Src, they appeared to have opposite roles in barrier regulation. Yes is required to create endothelial cell–cell contacts, whereas Src is required to break the contacts.

The differences between how Yes and Src regulate vessel leakage could be very important in drug development. It is likely that there are other Src-related phosphorylating proteins that have unique functions in the vasculature.

“A drug that specifically targets Src would strengthen the barrier and suppress leakage and edema. If you instead use a substance that broadly inhibits all Src-related phosphorylating proteins, which has been the strategy this far, it could prompt undesirable effects and possibly lead to disease propagation. In contrast, specific targeting of Yes would result in more vigorous leakage,” says Lena Claesson-Welsh.

The study has been published in the journal Nature Cardiovascular Research. It is a collaboration with scientists at the Department of Medical Cell Biology, Uppsala University and in Finland, Germany, Australia, Portugal and Scotland.

Article in Nature Cardiovascular Research

Lena Claesson-Welsh's research