Study raises important questions about the use of drugs that promote or prevent angiogenesis

Dartmouth Medical School cardiology researchers have discovered a new mechanism for what drives the growth of muscle tissue in the lining of injured heart vessels that can eventually lead to blockage.

Their study, reported in the October 19 issue of the journal Circulation, raises important questions about the use of drugs that promote or prevent angiogenesis-the formation of blood vessels-to treat the condition.

Normal heart arteries have a muscle tissue layer inside their walls. In coronary artery disease or in response to mechanical injury such as angioplasty (a non-surgical procedure to open clogged arteries), new smooth muscle cells grow along the innermost layer of the arterial lining and leads to narrowing. Such muscle buildup also occurs with use of a stent - a small wire mesh tube inserted after angioplasty to keep the artery clear.

It is the most common cause of stent failure, according to Michael Simons, professor of medicine and of pharmacology and toxicology at Dartmouth Medical School and chief of cardiology at Dartmouth-Hitchcock Medical Center, who headed the research team. Based on the research, Simons cautions against using angiogenic drugs to unblock arteries in certain heart conditions. He indicated that stents coated with agents that specifically target smooth muscle to prevent or kill growth should remain the treatment of choice at present. "They are not perfect, so everyone is looking for what can be added to make things better," he noted.

The biological drivers of the smooth muscle accumulation are unclear. Injury may somehow alter the tissue on the inner arterial layer, called the intima, so it is susceptible to factors in the blood that induce smooth muscle cells to proliferate. At the same time, there is an intense inflammatory response on the outermost layer of the arterial wall that also appears to be involved in stimulating blood vessels to feed smooth muscle accumulation.

Recent studies of the angiogenesis process have provided new insights into understanding cardiovascular disorders. Regulating angiogenesis with agents that promote or prevent blood vessel growth is considered a promising approach for treating a number of diseases. The researchers found that injured arteries grow smooth muscle in two distinct ways: one that depends on angiogenesis and another that is independent. "So even if no there is no angiogenesis, mechanical injury alone will still stimulate smooth muscle growth," Simons said.

This duality could make both angiogenesis-promoting and angiogenesis-suppressing drugs ineffective in preventing renarrowing of arteries following angioplasty or stenting. "In fact, pro-angiogenic drugs could make things worse, not better," Simons said. "If you're going to use an angiogenic agent, it will do harm, because it will actually promote stenosis [narrowing] instead of inhibiting it."

The studies were done in rabbits, chosen for their thick human-like arteries. Using an agent to stimulate angiogenesis on the outer surface after local injury, the researchers found a large increase in smooth muscle in the inside lining of the artery, meaning that angiogenesis induced intimal growth that narrowed the blood vessel. Then, using different agents to inhibit angiogenesis, they showed that even when angiogenesis was completely stopped, some new muscle accumulated.

"Intimal growth is a fundamental pathology responsible for many cardiovascular diseases including atherosclerosis and hypertension," Simons said. "This is the first time such a combination of angiogenesis-dependent and independent phases of smooth muscle growth has been proposed."

Study co-authors are Dr. Rohit Khurana, who was a visiting Fulbright scholar from University College London, Dr. Zhenwu Zhuang, Dr. Masahiro Murakami, and Dr. Ebo De Muinck, all from Dartmouth Medical School, as well as colleagues from London, Finland and Genentech of San Francisco.