Oxidants play major role in healing of damaged blood vessels

April 11, 2000

Researchers and clinicians have long labeled oxidants as villains in the fight against heart disease. But clinical trials using anti-oxidants against heart disease have been disappointing.

New research here is showing these same oxidants are critical for the healing of damage to the cardiovascular system and may tell us why anti-oxidants haven't worked.

Without the right mix of oxidants - also called "free radicals" -- at the sites of vascular injury, blood vessel walls won't heal. This finding offers one explanation for why antioxidant therapies haven't been effective in treating heart disease, as had once been hoped.

In a paper published in a recent issue of the journal Circulation Research, scientists at Ohio State University reported that endothelial cells adjacent to wounds on the inner surface of the vessel wall produced more oxidants than did identical cells farther away from the wound.

"We were looking at the possibility that when you stress endothelial cells, oxidants would be produced by these cells, damaging them," explained Pascal Goldschmidt, director of Ohio State University's Heart and Lung Institute. "Instead, we found that the oxidants are an important part of the repair process."

The report, led by Leni Moldovan, a postdoctoral fellow in Goldschmidt's laboratory, focussed on the endothelium, the layer of smooth cells that lines the walls of every blood vessel in the human body. In many forms of heart disease, damage to the endothelial wall is thought to be one initial cause. The buildup of lipid cholesterol in blood vessels, called atherosclerosis, can cause damage to the endothelial cell lining.

Goldschmidt and his colleagues took endothelial cells from the aortas of laboratory mice and grew them in tissue cultures. Using a tiny class pipette, they scraped across the surface of the cultured cells, mimicking a wound to the endothelium similar to one caused by the accumulation of cholesterol. Then they measured the concentrations of endothelial cell oxidants both at the edge of the "wound" and farther away from the scrape. The concentration of oxidants was much higher at the edge of the wound.

"The cells that were closest to the injury sensed that they had been stressed and started to produce increased amounts of free radicals," Goldschmidt said. "These free radicals are absolutely necessary to allow the endothelial cells to migrate and re-colonize the physical space opened by the wound."

The researchers discovered that the free radicals play a major role in enabling an endothelial cell to move towards a wound site.

Inside these cells, actin fibers form a type of scaffolding called the cytoskeleton, which helps the cells to maintain their structure. For the cell to move, the cell adds small actin subunits to the front of these fibrous polymers. At the same time, an equal amount of actin subunits is removed from the rear of these fibers. It is this constant assembly and disassembly that permits the cells to migrate to the site of an injury, Goldschmidt said.

An increase in oxidants at the site of an injury stimulates this intracellular construction. Likewise, they found that the addition of antioxidants would slow or stop the construction and therefore slow the cell migration and consequent wound healing.

"This might be the reason that the use of antioxidants has not been very successful for patients with heart disease," he said. The researchers believe that a fine balance is constantly being maintained in endothelial cells that keeps in check both the positive and negative aspects of oxidants.

While the oxidants sometimes kill healthy cells as part of the inflammatory process, they're also essential for the cells to perform repairs.

"We hope that we will eventually be able to find drugs that would be both really efficient at reducing the oxygen damage to coronary vessels without preventing the repair mechanisms arising from the oxidants," Goldschmidt said.

He envisions a time in the near future when people could take such drugs periodically to prevent the onset of vessel damage. Since more than half of the U.S. population above the age of 25 already shows signs of early atherosclerosis, this could be a major approach at reaching patients at risk for heart disease.

The National Institutes of Health, the American Heart Association and the Scleroderma Research Foundation provided support for this research.
Written by Earle Holland, 614-292-8384; Holland.8@osu.edu

Ohio State University

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