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 Journal of Cell Biology, 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 Cancer Biology at Mayo Clinic in Florida.
Physicians have attempted to regulate that pathway in cancer through use of VEGF inhibitors, such as Bevacizumab, 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 permeability of blood vessels.
Blood vessels are made up of endothelial cells 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 junctions 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 blood vessels 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.
Mayo Clinic: http://www.mayoclinic.org/news
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
At a recent event hosted by the Motion Picture Academy of Arts and Sciences, neuroscientists and cognitive psychologists got together with film makers to discuss what both groups have learned---the scientists through painstaking experiments and analysis, and the film makers by intuition and experience---about the mechanisms of attention and perception.
Yeast that can make opiates from other molecules raise the prospect of tanks of drug-producing microorganisms replacing open fields of opium poppies
Besides its wondrously alien look, the coolest thing about the Portuguese man-of-war is that it is not an individual animal at all, but an entire community
A Maine teenager and her father have landed a one-in-two-million catch - a blue lobster.
The equations that describe these movements are equivalent to those that govern waves
The famed bird now finds itself at the center of a flap over de-extinction
Excess heat being stored hundreds of metres down in Atlantic and Southern oceans not Pacific as previously thought
Researchers created visual and DNA analysis of how anoles regenerate their tails.
My father worked for over 30 years in construction, falling off of ladders and getting slivers of metal in his eye and generally bleeding profusely. He toiled like a maniac so our family could eat, all while furthering one of humanity’s most indispensable inventions: large-scale construction of shelter.
Birds lost the taste receptors for sugar, but hummingbirds clearly have a sweet tooth. Now we know how they regained it