Getting to the Heart of Atherosclerosis

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It's an insidious process, beginning at an early age. The linings of our arteries begin to show the wear and tear of living. Thin, fibrous patches on our arterial walls begin to form and gradually become more widespread over the years. In some people, the process goes out of control. Large, hard, yellow masses called plaques begin to form, constricting the arteries. The process is known as atherosclerosis, and it is the primary cause of cardiovascular disease, the leading cause of death in the United States.

When atherosclerosis blocks the coronary arteries, a heart attack can be the result. But the condition can occur elsewhere in the body with similarly devastating effects. In the legs, it can make walking painful and difficult. When it occurs in the carotid arteries of the neck, which supply blood to the brain, atherosclerosis can lead to stroke.

The UW School of Medicine has the largest research program on atherosclerosis in the country. Researchers there not only have been studying what causes these changes in the structure of the arterial wall, but also have developed new and innovative ways to diagnose, prevent, and treat the condition.

UW professors Russell Ross and John Glomset are credited with formulating the dominant hypothesis about what causes atherosclerosis. Ross is a professor of pathology and director of the UW's Center for Vascular Biology; Glomset is a professor of medicine and biochemistry.

Ross and Glomset hypothesized that atherosclerosis occurs in response to localized injury to the lining of the artery wall. That injury in turn causes a proliferation of smooth muscle cellsthe elongated, spindle-shaped cells that make up the artery wall. The initial injury may be brought about by any of a number of causes, including viruses, high cholesterol, smoking, diabetes, or oxidized fatty acids.footnote 1comma footnote 2

What may be the body's way of trying to heal itself may end up being counterproductive as the proliferation of cells leads to a blockage. This revolutionary "Response-to-Injury" hypothesis was first published in 1973 and has since given rise to a host of research projects at the UW and around the world. "The UW School of Medicine is one of the few institutions that covers the entire spectrum of research on atherosclerosis, from its cellular origins to its clinical aspects," notes Ross. "This puts the school's researchers in a powerful position to study the disease."

Although atherosclerosis is a complex process, it appears that three main steps contribute to lesion formation: the smooth muscle cells in the artery wall begin to proliferate; connective tissue forms; and lipids, or fats, accumulate in and around the cells. Ross believes the process begins when cells on the surface of the artery wall become damaged, and begin to interact with circulating white blood cells called monocytes. The monocytes adhere to the wall, migrate underneath the surface layer, and change into scavenger cells, called macrophages. Some of the macrophages collect lipids until their insides take on a foamy look with included fat globules--hence the name "foam cells."

The foam cells help create a swelling in the artery wall called a fatty streak. Ultimately, the layer covering the fatty streaks separates and exposes the once-hidden foam cells to the circulating blood, allowing platelets to stick to the foam cells and to underlying connective tissue. These fatty streaks may set the stage for worse to come, as platelets from the circulating blood adhere to the exposed tissue and release a number of potent chemical messengers that can alter the metabolism of the smooth muscle cells in the artery.

One of those messengers is platelet-derived growth factor (PDGF), which Ross discovered in 1974. Acting as a sort of cellular Pied Piper, the PDGF stimulates cell division and chemically attracts smooth muscle cells to the lesion site. In 1991, Ross and colleagues demonstrated in animal studies that by neutralizing the growth factor's activity, they could hinder the migration of smooth muscle cells. Alan Chait, a professor in the division of metabolism, endocrinology, and nutrition of the UW School of Medicine, further demonstrated that PDGF may also increase the binding of fatty substances called low density lipoproteins to the surface of smooth muscle cells.

PDGF has turned out to be one of the most important growth factors; it controls proliferation of a variety of cells, including connective tissue. It is also now known as a prominent factor in cells of the central and peipheral nervous system.

  1. "The Root of Atherosclerosis," Leila Gray, Medicine Northwest, Winter 1985, p. 15.
  2. "The Pathogenesis of Atherosclerosis," Russell Ross and John A. Glomset, New England Journal of Medicine, 295, 369 & 420, (1976).

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