Shutting off plaque's lifeline of blood.

Plaques, the gummy, blood vessel deposits that are central to heart disease, are usually considered just artery-clogging lumps. However, plaques often contain living cells in need of nutrients. New, minuscule blood vessels appear near plaques to provide those supplies.

A study of mice now shows that drugs known to curb vessel growth seem to starve plaques, suggesting a tantalizing way to battle heart disease. The compounds are already being tested as weapons against cancer.

In a report in the April 6 Circulation, researchers describe a study of 47 mice that were bred to have a humanlike susceptibility to plaque formation. Their food mimicked the diet consumed by people in the United States. When the mice were 20 weeks old, the researchers pulled 10 out of the group and measured the plaque that had accumulated in each animal's aorta, the large artery leading out of the heart.

For the next 16 weeks, some of the remaining mice received alternate-day doses of drugs that inhibit new vessel growth. Ten received a protein called endostatin, and 15 got a synthetic compound called TNP-470. Twelve other mice received inert injections.

Compared with the mice analyzed earlier in the experiment, all these mice had more plaque--three times more in the case of the untreated mice. However, the mice getting TNP-470 showed a more modest 60 percent increase, while those given endostatin experienced plaque growth of only 28 percent, says study coauthor Karen S. Moulton, a cardiologist at Brigham and Women's Hospital and Children's Hospital, both in Boston.

"It's a very intriguing study," says Jan L. Breslow, a cardiologist at Rockefeller University in New York. "It suggests that one can limit the growth of large plaques through angiogenesis inhibition."

Angiogenesis, or new blood vessel growth, is currently an area of intense research. Scientists suspect that heart muscle damaged in heart attacks might be salvageable if angiogenesis can be harnessed to feed blood to those areas.

In contrast, other researchers want to stifle blood vessel formation in order to cut off nutrient supplies to tumors.

The explanation proposed for the drugs' effects on plaque is complex. Beyond limiting nutrients available to plaque's fat and collagen cells, endostatin and TNP-470 may shrink plaque by hampering the activity of roving immune cells called macrophages, Moulton says.

These cells normally react to plaque-caused lesions on a vessel wall by bundling up cellular debris in the area, recruiting other cells, and performing various housekeeping duties. However, in a blood vessel chronically abused by excess cholesterol, residues of cigarette smoke, or high blood pressure, macrophages may do more harm than good, Breslow says. In particular, macrophages induce vessel growth that could nourish plaque cells and provide an avenue for additional cells that may swell the plaque, Moulton adds.

The greatest danger of plaques arises when they rupture, attracting platelets that can form blood clots. The largest plaques aren't always the ones that rupture, so physicians don't know which plaques to watch.

Thus, a broad preventive approach that thwarts angiogenesis may work, Moulton says. "Shutting off the portal of entry of inflammatory cells may slow [plaque formation] down," she says.

Ironically, if angiogenesis-promoting and angiogenesis-inhibiting drugs become available for human use, many patients might be candidates for both: one to reverse heart-muscle damage and the other to limit plaque growth. Angiogenesis stimulants last only a short time, whereas the angiogenesis inhibitors seem to work for months, at least in mice. These "different kinetics" may avert the conflict, Moulton says.