Stockholm -- Basic research into angiogenesis is shedding new light on the mechanism of atherosclerotic plaque growth and ultimately may lead to the development of new treatments for atherosclerosis, according to Dr Judah Folkman (Harvard Medical School, Boston).

In a plenary lecture delivered at the XIIth International Symposium on Atherosclerosis, Folkman described the latest findings from research into the mechanism of plaque growth, presented new insights from cancer clinical trials, and gave an overview of fast-moving clinical trials using angiogenesis inhibitors to treat eye disease.

Just 7 years ago, there was no research into angiogenesis and atherosclerotic plaques, Folkman pointed out. Since that time, a series of issues have been addressed in the laboratory, from the development of an animal model to the discovery that plaques have new blood vessels. At present, the key step in research has been to demonstrate that plaque growth in mice is dependent on new blood vessel growth, according to Folkman.

"Plaque growth appears to be angiogenesis-dependent," he said. "Studies in mice have shown the principle that plaque growth is dependent on blood vessel growth and that's probably true in humans, but you could never show that in humans."

Until 1993, atherosclerotic plaques were thought to be inert, with vessels that were invisible to pathologists. But then, scientists developed immuno-labeling techniques to stain and "light up" blood vessels. They were then able to stain plaques and, as Folkman said, "Suddenly, you saw blood vessels through them, like a forest."

Trials With Angiogenesis Inhibitors

In Folkman's laboratory, Dr Karen Moulton has conducted research into plaque growth for the past 5 years using two different angiogenesis inhibitors, endostatin and TNP-470. These two agents currently are being used in clinical trials to treat cancer. Her experiments began after Dr Jan Breslow (Rockefeller University, New York) developed an animal model which could develop arterial plaques. These mice are deficient in apolipoprotein E, (apoE), one of the major plasma apoproteins involved in cholesterol transport and redistribution.

Moulton's latest study has found that endostatin inhibits plaque growth during the treatment period by 85%, while TNP-470 inhibits plaque growth by 70%. In the experiment, apoE-deficient mice were fed a high-cholesterol western-type diet for 20 weeks; they consequently developed massive lesions. At 20 weeks, the mice were divided into 3 groups. One group was treated with endostatin, a second group was treated with TNP-470, while a third group served as controls.

"Prolonged treatment with either angiogenesis inhibitor reduced plaque growth and intimal neovascularization in apoE deficient mice," Moulton stated.

In his address, Folkman said "chronic anti-angiogenic therapy may not have an adverse effect on myocardial ischemia and could have a beneficial effect by suppressing plaque growth."

Anti-Angiogenesis May Be Key to Multiple Conditions

He referred to current clinical trial data with angiogenesis inhibitors in seriously ill cancer patients who have failed all other therapy. The cancer trials using endostatin and TNP-470 have not reported any adverse events involving the heart so far, according to Folkman.

Earlier, there was a question whether or not angiogenesis inhibitors might turn off collateral blood vessels in the heart and create problems. But, "The answer is no, they turn off the small blood vessels in the plaque," Folkman said. He predicted there would be no adverse events involving the heart in these cancer patients but cautioned that it could take up to 10 years for events to occur.

"One would like to see human trials with angiogenesis inhibitors to treat early atherosclerosis," Folkman said, "but it is too early from a technical point of view." There are long waiting lists of more than 1000 patients who want to receive endostatin for cancer treatment, he pointed out. At present, only enough endostatin is produced to treat about 100 patients in cancer clinical trials. Folkman also noted that this presents an ethical dilemma in medicine everywhere in the world whenever new molecules are being tried in small numbers of humans.

In another aspect of clinical research with angiogenesis agents, there are now 5 phase III trials in the treatment of eye disease which Folkman said are "based on the principles that came from cancer." Although the trials in eye disease started later than the cancer trials, they've now moved ahead. These trials use angiogenesis agents to treat either macular degeneration or diabetic retinopathy.

"The big surprise is by studying angiogenesis in cancer, you find out that the oncologists are using an angiogenesis inhibitor and are treating the same abnormal blood vessels as the ophthalmologists who are treating the eye, or the gynecologists who are treating endometriosis, or the pediatricians who are treating hemangiomas," Folkman said.

New Cardiovascular Techniques

In atherosclerotic disease, Folkman suggested that in the future it might be possible to use local anti-angiogenic therapy against the neovascularized plaque in the coronary arteries. He explained, "Potentially, it's possible during angioplasty to insert a gene or plasmid for an angiogenesis inhibitor, such as endostatin."

Another new technology, using a catheter to determine whether a plaque has blood vessels or not, is just beginning to be studied, according to Folkman. Experimentally, an infrared detector has been put at the tip of a catheter to determine whether or not it is possible to advance the detector through a plaque and learn if the lesion contains vessels.

"Cardiologists may be able to inhibit neovascularization in plaques and still grow new vessels in the wall of the heart," Folkman said. "There is the potential for exciting advances in both cardiology and angiogenesis research."

Pat Phillips
www.athero.org