Study unravels biological pathway that controls the leakiness of blood vessels

(Medical Xpress)—A research team led by scientists at Mayo Clinic in Florida have decoded the entire pathway that regulates leakiness of blood vessels—a condition that promotes a wide number of disorders, such as heart disease, cancer growth and spread, inflammation and respiratory distress.

They say their findings, published online Dec. 17 in the , suggest that several agents already being tested for other conditions might reverse vessel leakiness.

"Now that we understand a lot more about the pathway that leads to leaky blood vessels, we can begin to try to target it in an efficient way, and that is very exciting," says the study's lead investigator, Panos Z. Anastasiadis, Ph.D., chair of the Department of at Mayo Clinic in Florida.

Physicians have attempted to regulate that pathway in cancer through use of VEGF inhibitors, such as , but these drugs are not as effective as they might be if other parts of the pathway were also inhibited, Dr. Anastasiadis says.

The research team, led by Dr. Anastasiadis and Arie Horowitz, Ph.D., at Cleveland Clinic Foundation, found that VEGF is one of two different molecules that affect a key downstream protein, Syx, to regulate the of blood vessels.

Blood vessels are made up of that have to fit tightly together to form a solid tubular structure that blood can flow through. The researchers discovered that VEGF turns off Syx, which normally ensures the junctions between endothelial cells are strong. Without Syx, adhesion between the cells is loose, and the blood vessels are leaky. When new blood vessels are needed—such as to feed a growing tumor—VEGF loosens up endothelial cells so new vessels can sprout.

Then, after new vessels are formed, a second molecule, angiopoietin-1 (Ang1) works to glue the cells back together, Dr. Anastasiadis says. "These molecules have opposing, yin and yang effects. VEGF kicks Syx out of the between cells, promoting leakiness, and Ang1 brings it back in to stabilize the vessel," he says.

The issue in cancer, however, is that VEGF overwhelms the system. "There isn't enough Ang1 to glue the vessels back together, and this leakiness allows cancer cells to escape the tumor and travel to other parts of the body," Dr. Anastasiadis says. "In late stages of the cancer, it also promotes the leaking of liquids into organs, such as the lungs. This results in profound effects that are often lethal."

Other disorders, such as inflammation and sepsis, a deadly bacterial infection that can result from excess liquid in lungs, are also induced by a leaky vascular system, he says.

Based on a detailed analysis of molecules involved in the VEGF/Ang1/Syx pathway, Dr. Anastasiadis believes that several experimental agents might help reverse vascular leakiness. One of them inhibits protein kinase D1 (PKD1), which might prevent endothelial cells from coming apart from loss of adhesion, and the other is a Rho-kinase inhibitor that prevents endothelial cells from contracting—which they must do to loosen up and become leaky.

"We now have new directions for both further basic research into leaky and for potential clinical treatment," Dr. Anastasiadis says.

Investigators from Johns Hopkins University, Dartmouth Medical School, and Case Western Reserve University also contributed to the study.

Related Stories

Normalizing tumor vessels to improve cancer therapy

Aug 25, 2008

Chemotherapy drugs often never reach the tumors they're intended to treat, and radiation therapy is not always effective, because the blood vessels feeding the tumors are abnormal—"leaky and twisty" in the words of the ...

Recommended for you

Unlocking the secrets of pulmonary hypertension

7 hours ago

A UAlberta team has discovered that a protein that plays a critical role in metabolism, the process by which the cell generates energy from foods, is important for the development of pulmonary hypertension, a deadly disease.

New molecule sneaks medicines across the blood/brain barrier

12 hours ago

Delivering life-saving drugs across the blood-brain barrier (BBB) might become a little easier thanks to a new report published in the November 2014 issue of The FASEB Journal. In the report, scientists describe an antibo ...

User comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.