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8/22/93
Blood Vessels Feel Shear Stress of Blood Flow

Chicago, Ill. -- The whoosh, whoosh, whoosh of blood coursing through the human body has fascinated scientists since long before Harvey identified the heart as the body's pump.
Now a Penn State researcher is looking at how the blood vessels, the pipes of the system, react to shear stresses caused by blood flow.
"It is really a two-part process," says Dr. John A. Frangos, associate professor of chemical engineering. "We need to know how the diameter of blood vessels effects blood flow and how blood flow effects the vessels."
As early as 10 years ago, researchers knew that a molecule produced by the endothelial cells lining the blood vessels was a dramatic relaxer of the blood vessel walls. What they could not do was identify this molecule. They called it "endothelial derived relaxing factor" or EDRF.
"About three years ago, researchers identified EDRF as the free radical nitric oxide which exists for very short periods of time," says Frangos. "This short half-life is the reason that nitric oxide was so difficult to identify."
Researchers now know that this simple molecule composed of one oxygen atom and one nitrogen atom acts not only to relax the blood vessels, but also is implicated in diabetic retinal deterioration, blood pressure control, memory, male impotence and endotoxic shock.
"We know that if a blood vessel senses an increase in blood flow rate, then the blood vessel will dilate, but what we need to understand is how this mechanism works," Frangos told attendees at the 206th national meeting of the American Chemical Society in Chicago, Aug. 22-27.
The second part of this equation was the discovery of Endothelin-1, a larger molecule consisting of 21 amino acids that has diametrically opposite properties to nitric oxide. ET-1 causes blood vessels to constrict and makes vessel walls thicken.
"Previous studies confirmed by our experiments have shown that increased blood flow increases the production of nitric oxide," says Frangos. "The strangest thing about the mechanism behind ET-1 is that well-respected researchers have found that blood flow both stimulates the production of ET-1 and suppresses the production of ET-1.

"We have shown that both sets of researchers are correct."

Frangos is using a specialized system consisting of a parallel plate flow chamber driven by a flow loop to test the effects of shear stress on blood vessels. Human endothelial cells obtained from the large vein in discarded umbilical cords of newborns are plated onto the plates in the system, mimicking the lining of the blood vessels. A mixture of saline solution and proteins is used to simulate the blood flowing through the system.

"Blood is a viscous fluid and as it flows through the blood vessels there is hydrodynamic drag acting on the vessel walls," says Frangos. "We create this frictional force in the experimental system without any extraneous interference such as the chemical interaction of blood platelet cells with the cell wall."

Frangos' systems allows monitoring of the production of nitric oxide and ET-1 throughout changing flow regimens and shear stress.

"Using flow rates one expects to see in sick people or mimicking a situation where a clot blocks the flow and suddenly kicks free, we see significant production of ET-1," he adds. "This release of ET-1 constricts the vessels and makes the situation even worse than it was before."

In a healthy situation, for example that of a person going from sitting to running, there is a burst of ET-1, but also a burst of nitric oxide. The nitric oxide negates the effects of ET-1. When a person sits suddenly, there is a burst of nitric oxide and a relaxation of the blood vessels also.

"Our experiments show that there is a link between nitric oxide and ET-1," says Frangos. "We see that increased flow increases nitric oxide production and nitric oxide production suppresses ET-1.

"The really curious thing is why the ET-1 response is only seen in pathological situations. We have not, as yet, found any normal physiological relevance for this response."

While Frangos has shown the effects of shear stress on blood vessels, this type of physical action also effects some types of bone cells. Even plant cells respond to physical forces such as wind.

"We want to know how a living cell senses motion or force," says Frangos. "We know that when we block the action of G-proteins in cells we block the effects of shear stress."

G-proteins are the molecules inside the cell that react when hormones on the outside of the cells bind to hormone receptor sites.

"What we don't know is if shear stress acts directly on the G-proteins, on the hormone receptors or on other, as yet unidentified sites on the cell membrane."

*aem*

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