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Protein S production discovered in endothelial cells

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http://www.medindia.net/news/Protein-S-Hel...els-57434-1.htm

Protein S Helps in Formation of Healthy Blood Vessels

Researchers at the Salk Institute for Biological Studies have discovered that CA?Protein S, a well-known anticoagulant protein, keeps the blood flowing in more than one way. The protein contributes to the formation and function of healthy blood vessels. The researchers found that mice lacking protein S suffered massive blood clots, but also had defective blood vessels that allow blood cells to leak into the surrounding tissue.

"We had anticipated finding clotting problems, but the prominent role of protein S in the development and maintenance of blood vessels was completely unexpected," says first author Tal Burstyn-Cohen, Ph.D., a former post-doc in the Molecular Neurobiology Laboratory and now at the Department of Ophthalmology, Hadassah Medical Center, Jerusalem, Israel.

There are more than 200 known human mutations and polymorphisms in the gene coding for protein S, which was arbitrarily named after Seattle, the city of its discovery. The resulting deficiencies predispose carriers to deep venous thrombosis, strokes at an early age, recurrent miscarriages, and pre-eclampsia, and are associated with several autoimmune diseases, most prominently systemic lupus erythematosus.

"Protein S is a really interesting molecule," says Greg Lemke, Ph.D., a professor in the Salk's Molecular Neurobiology Laboratory, who led the study, which appears in the Sept. 1, 2009, issue of the Journal of Clinical Investigation. "During the course of evolution, it was co-opted from the coagulation cascade for the regulation of inflammation in the immune system."

The moment a blood vessel is breached, the coagulation cascade activates a series of enzymes in domino-like fashion, which allows the rapid formation of a plug at the site of injury. As part of a carefully calibrated system of checks and balances, Protein S aids with the inactivation of clotting factors Va and VIIIa, preventing excessive clotting.

In patients who are born with two abnormal copies of the protein S gene, a severe form of thrombosis called purpura fulminans can result. This life-threatening condition involves severe clotting throughout much of the body, ultimately causing death to the tissues.

But Protein S also binds to and activates a trio of receptors, Tyro3, Axl, and Mer, which are collectively known as TAMs. Apart from being involved in a host of cellular processes, the TAMs most famously act as a molecular "trip switch" that prevents the immune system from spiraling out of control and turning against one's own body.

Though protein S's dual role in coagulation and inflammation is one that scientists have known about for years, its exact function has remained a mystery. Lemke and Burstyn-Cohen, wanting to understand the molecular details, created knockout mice missing the ProS1 gene, which encodes protein S.

"It was the last gene encoding a critical component of the blood coagulation cascade to be inactivated in mice," says Burstyn-Cohen, "and the resulting phenotype is probably the most severe of them all." Mice without functional protein S die in utero with massive consumptive blood clots, which soak up all available clotting factors, causing severe hemorrhaging elsewhere.

In addition to blood clots, these mice also had problems with vascular integrity and the functioning of these blood vessels. "TAM receptors are important for maintaining the physiological integrity of the smooth muscles that line blood vessels," explains Burstyn-Cohen. "Without protein S the muscle layer is disordered, and the vessels become leaky."

Like other components of the clotting cascade, most of the circulating protein S is produced by hepatocytes in the liver, or so it was thought. When Burstyn-Cohen shut down the production of protein S in hepatocytes, however, levels of protein S only dropped by half. A closer look revealed that the endothelial cells lining blood vessels themselves provided most of the remaining protein.

"Blood clotting disorders are a good target for gene therapy since the absence of a single factor can sabotage the body's ability to stanch bleeding or stop the coagulation process," says Lemke. "Our findings suggest that in addition to hepatocytes, endothelial cells, which are easily accessible via the circulatory system, may be a particularly good target for gene therapy to correct genetic or acquired defects in ProS or other regulators of blood coagulation."

Source-Eurekalert

RAS

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Interesting research, I had a hematologist during the early stages of my PSD who believed venous endothelial cells

were involved in Protein S formation. He felt that the extensive balloon venoplasty I had done would strip these

tissues from the cell walls. It saves one in the short run but will insure a decreased or altered formation of

Pro.S in the future. He preferred bed rest and "clot busting" drugs like TPA to the aggressive removal of clots.

It also explains the twisted, branching nature of collateral circulation that formed around

my Inferior Vena Cava filter that was clotted. These veins appear on the surface of both sides of my abdomen

as engorged and very twisted curvy varicose veins. Often in my legs, abdomen, or in deeper viens I will have a knotted formation of these

veins that seem to thrombose (despite an INR maintained at 2.6 or above)

and cause a red inflamed hot streak that eventually looks bruised and forms a hard rope

feeling mass, then makes new circulation around the area. They seem like infected throboses, but always

respond to anti-inflammatory drugs but not to antibiotics. It seems that the early stage of formations of these venous

blockage could be an auto-immune type inflammation rather than a blood clot.

Perhaps this research will lead to some stem cell type

of research, such that these faulty or missing tissues can be urged to reproduce.

Thank you for the update, i'll keep my ear to the rails for some advances along these lines.

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