Apr. 6, 1999 DALLAS, April 6 -- Treatment of mice with substances that halt the growth of blood vessels inhibited the development of artery-clogging deposits known as plaque, as well as the tiny blood vessels that may nourish the plaque, according to a study reported in today's Circulation: Journal of the American Heart Association.
"These early results in animals suggest that the development of certain tiny new blood vessels within plaque may contribute to the progression of heart disease," says lead author Karen S. Moulton, M.D., of Brigham and Women's Hospital and Children's Hospital and cardiology instructor at Harvard Medical School in Boston.
"If this finding is supported in future studies, blood vessels in plaque could provide a potential target for the design of treatments that can delay the progression of heart disease and possibly reduce the incidence of heart attacks and strokes," Moulton adds.
In this study, mice that already had plaque in their arteries were given endostatin, a substance previously shown to inhibit development of new blood vessels. The treated mice averaged an 85 percent reduction in the volume of plaque growth compared to untreated animals of the same strain. Mice treated with another inhibitor, TNP-470, averaged a 70 percent reduction in the volume of plaque growth during the treatment period compared to untreated animals, says Moulton.
The research reported today was supported by the National Heart, Lung, and Blood Institute and was conducted at the Children's Hospital in Boston in the laboratory of Judah Folkman, M.D., a pioneer in the field of research on angiogenesis, the development of new blood vessels in the body.
During the past 15 years, researchers have discovered a host of natural molecules in humans that either stimulate or retard angiogenesis. Angiogenesis inhibitors are currently being tested in humans to determine their effectiveness in treating some cancers that require blood vessels in order to grow. These agents are also being investigated in studies of humans who have a type of sight-robbing macular degeneration associated with the proliferation of abnormal new blood vessels in the eye.
While angiogenesis inhibitors are being used in cancer and vision research studies, heart disease investigations are focusing on angiogenesis promoters. In the heart research, scientists are testing in humans certain genes and their protein products that promote angiogenesis. The goal of this research is to circumvent coronary arteries obstructed by the plaque deposits that characterize atherosclerosis, the disease process that causes heart disease.
Very tiny blood vessels called capillaries can grow from the artery wall and invade plaque. Whether these vessels promote plaque growth is uncertain. The Circulation paper provides the "most persuasive evidence to date" that these new blood vessels are a prerequisite for plaque expansion, says Jeffrey M. Isner, M.D., in an editorial accompanying the paper. Isner is chief of vascular medicine and cardiovascular research, department of medicine, St. Elizabeth's Medical Center, Boston, and professor of medicine and pathology, Tufts Medical School, Boston.
Does this evidence suggest that gene and protein treatments designed to promote angiogenesis in people with heart disease could result in the development of larger plaque in these individuals?
Recent human and animal studies on angiogenesis and heart disease have not revealed plaque growth as a result of these treatments, says Isner, one of several scientists conducting this type of research.
The mice in this experiment were fed a "Western diet," which is designed to mimic the cholesterol content of the typical diet eaten in the United States. The amount of plaque the mice developed was measured in the aorta, the large artery that carries blood from the heart to the rest of the body.
A group of 20-week-old mice was divided into three groups and treated for 16 weeks. One group received endostatin, another TNP-470, and the third was injected with saline solution and served as a control group. At age 36 weeks, the average cholesterol levels of the three groups were about the same.
However, there was a significant difference in plaque accumulation between the treated and untreated animals. Prior to treatment with the angiogenesis inhibitors, the average area of plaque lesions was 0.250 square millimeters (mm2). At the end of the treatment period, the control group had an average plaque area of 0.751 mm2, compared to 0.321 mm2 for the group treated with endostatin and 0.402 mm2 for the TNP-470 group. Chronic treatment with either endostatin or TNP-470 appeared to inhibit plaque growth by 85 percent and 70 percent respectively, the researchers report.
When the research team delayed the same treatments until the mice were 32 weeks of age, they found smaller but still significant differences in plaque growth between the treated and untreated groups.
Finally, mice treated for 16 weeks, starting at age 6 weeks, showed no significant differences in plaque growth between the treated and control groups. Young mice do not yet have blood vessels growing into their forming plaques, says Moulton. The thicker the plaque, the more likely they are to contain blood vessels. Twenty-eight percent of the plaque deposits greater than 250 microns thick, roughly four times the width of a human hair, contained blood vessels. Less than 3 percent of plaque deposits between 100 and 250 microns had vessels in them.
"In our studies, the animals did not develop any significant adverse side effects. They gained weight, and I did not observe any other measurable health effects," says Moulton.
"More basic research is needed to determine the mechanism responsible for stimulating the tiny blood vessels that enter the artery and to understand the role of these vessels in boosting plaque growth and promoting plaque disruption," adds Moulton.
Additional research also is needed to address the possible limitation of using angiogenesis inhibitors to reduce plaque growth, says Isner. The results thus far, he explains, suggest a "relatively narrow window of opportunity" for the inhibitors to be effective. They were minimally effective, he says, during the early stages of plaque development and after 32 weeks in the study.
Isner notes that "the laboratory that has for the last third of the 20th century established itself as the cradle of angiogenesis has given us once again important, challenging, and intriguing homework to carry us into the next millenium."
Study co-authors are Eric Heller, M.S.; Moritz A. Konerding, M.D.; Evelyn Flynn, M.S.; Wulf Palinski, M.D.; and Judah Folkman, M.D.
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