Stabilizing Plaque in Blood Vessels

If human beings waited until they were 80 to reach sexual maturity, they would stay healthier a lot longer. The evolutionary logic is straightforward: the goal of any organism is to pass its genes to the next generation. Natural selection favors organisms that develop strategies to help them survive until they can reproduce. How organisms adapt to events that happen afterward is a matter of no concern.

The fate of smooth muscle cells is a case in point. Found in the walls of the blood vessels, they have evolved to perform two primary functions. Under everyday conditions, smooth muscle cells contract and dilate, helping to regulate the distribution of blood. When a blood vessel is damaged by a wound or injury, the cells change form and lead the effort to repair it. “From an evolutionary point of view, both of these functions are critical to allow people to survive at least until their reproductive years,” says Gary Owens, a professor of molecular physiology and biological physics.

Unfortunately, as people age, they tend to develop fatty plaques within the walls of their blood vessels, a process that is exacerbated by smoking and the rich diet that typifies many developed countries. When these plaques rupture, they release tissue that can block blood vessels in the heart, causing a heart attack. Because this process, known as atherosclerosis, typically does not cause harm until people enter their 50s, there is no evolutionary pressure to correct it. Smooth muscle cells, evolved for other purposes, have to cope with this plaque as best they can with the mechanisms they have available to them.

In most cases, the smooth muscle cells adapt well, producing substances that form a fibrous cap that contains the plaque and creating a matrix that stabilizes it. In some situations, however, the cells lose their protective ability, and paradoxically begin to secrete substances that dissolve these fibrous caps. When this happens, the plaques become unstable and are prime candidates for rupture, the underlying cause of heart attacks. One of the projects of Owens’ laboratory is to find out why the smooth muscle cells undergo this transformation.

Working with Matthew Alexander, an M.D./Ph.D. student, Owens is tracing the biochemical signals at the root of this process. They found that unstable plaques are characterized by a large number of proteins that cause inflammation. One of these, interleukin-1 beta, is produced by macrophages, a specialized immune system cell. In experiments, they have found that interleukin-1 beta suppresses the genes in the smooth muscle cells that help stabilize the plaques and activate genes that weaken the fibrous cap.

In Owens’ view, this research has enormous potential. “We are looking at small molecule inhibitors of interleukin-1 beta that would reduce the probability of plaques becoming unstable and rupturing.” Such inhibitors could be taken on a daily basis to stabilize atherosclerotic plaques and reduce the possibility of a heart attack. Such a molecule may also be the key to treating a number of other ailments, in that the transformation that the smooth muscle cell undergoes, called phenotype switching, is implicated in asthma, cancer, bladder dysfunction, and reproductive disorders as well as in atherosclerosis.