Cholesterol and other lipids make up the membranes of all cells. The exact amount of cholesterol in the membranes of a cell must be carefully regulated, or else the membranes will be too stiff, too leaky, or too tight, and the cell will die.
There are two key facts about cholesterol that will help you understand why cells in an atherosclerotic lesion have such problems with it. First, cholesterol cannot be disassembled, hydrolyzed, or oxidized away by cells, as other molecules such as fats and glucose can be. (Actually cholesterol can be oxidized to a very limited extent, but less than one hundredth of all the cholesterol in atherosclerosis is oxidized.) Second, all of the cholesterol in a cell will find its way into membranes; it is not stored outside of membranes.
If a cell has too much cholesterol, it can do two things to avoid death. A cell can link cholesterol with a fatty acid by a chemical ester bond, making cholesterol ester (sometimes called cholesteryl ester). Cholesterol ester does not get into cell membranes in substantial amounts. Cholesterol ester can be stored away inside the cell, and even in large amounts cholesterol ester does not kill the cell. There is probably some limit on how much cholesterol ester can be stored away, but the entire cell may fill up with it, becoming a foam cell, and even enlarge to a ridiculous size.
The second thing that a cell can do with cholesterol is to ship it out by transferring cholesterol to high density lipoproteins (HDL). HDL accept the extra or excess cholesterol from cells. HDL have a very important role to play in the arterial intima, because HDL can carry excess cholesterol from intimal macrophages back across the endothelial cells, into the bloodstream, and eventually back to the liver. This is called "reverse cholesterol transport." The liver is usually able to get rid of any extra cholesterol the body has made.
Atherosclerosis can be viewed as a race between LDL, bringing cholesterol into the arterial intima, and HDL, removing cholesterol from the arterial intima. LDL have a simpler function. LDL cross the endothelial barrier and get trapped in the arterial intima. The cholesterol in LDL is eventually dumped in the intima, and the intimal cells have to deal with it. HDL have a harder job. HDL must cross the endothelial barrier, interact with macrophages and perhaps smooth muscle cells, pick up cholesterol, and carry the cholesterol back across the endothelial barrier. No wonder that atherosclerosis almost always tends to get worse as time goes by; only rarely does atherosclerosis regress and improve.
Smooth muscle cells in atherosclerosis
If not for smooth muscle cells, the intimal and medial layers of the artery wall would not be connective tissues (see 4th paragraph in "The Normal Artery" discussed earlier). Smooth muscle cells differ from the regular, skeletal muscle cells found in the biceps and other muscles around the body. First, smooth muscle cells do not have the striated, or train-track, appearance of skeletal muscle cells. That is why they are called "smooth." More importantly, smooth muscle cells are not as specialized as skeletal muscle cells. In the arterial wall, smooth muscle cells contract and relax, and they also manufacture large amounts of collagen, elastin, and proteoglycans that give extra strength to the artery and give it the characteristics of a connective tissue.
Most connective tissues in the body are built by cells whose primary purpose appears to be manufacturing collagen and other fibrous proteins. These cells are called fibroblasts, and they are the majority of cells found below the skin and in tendons. Why do smooth muscle cells instead of fibroblasts perform this task in the artery wall? The ability of the smooth muscle cell to contract and to relax appears to be important for arteries to grow and develop properly, since the tissue is constantly under tension, because of arterial blood pressure. Furthermore, the smooth muscle cell's intimate connections with fibrous tissue proteins assure that the whole tissue bears the tension properly. And under certain conditions, the artery wall can relax and gradually expand even in an adult animal. We'll come back to this concept later when we discuss the interaction between endothelial cells and smooth muscle cells in determining arterial diameter.
Two major bad things and one major good thing happen to smooth muscle cells in atherosclerosis: they die (bad), they grow back over dead areas (good), and sometimes they produce fibrous scars that close down the flow of blood in the artery (bad). In addition, smooth muscle cells can participate in inflammation by making signaling molecules that influence the other arterial cells.
The death of smooth muscle cells in the core of atherosclerotic plaques is critical to the weakening of the plaque that leads to rupture and blood clotting. Smooth muscle cells make and maintain the fibrous tissue proteins. With smooth muscle cell death, the ability to repair gaps in the tissue is lost. As mentioned above (see "Progression of Atherosclerotic Lesions" above), smooth muscle cells may die because they take in too much cholesterol. The intense deposition of cholesterol outside of cells may kill nearby cells, as tiny amounts of cholesterol dissolve in water around the deposits and move through the water to nearby cell membranes. Another theory about smooth muscle cell death in atherosclerosis suggests that oxidized cholesterol (specifically, hydroperoxy-cholesterol) kills the cells. Hydroperoxy-cholesterol in very small amounts is toxic to cells. Hydroperoxy-cholesterol is formed by a reaction between cholesterol and oxygen dissolved in body fluids. Antioxidants might be able to slow this reaction, whereas antioxidants would likely have no effect on cholesterol-induced smooth muscle cell death.
In atherosclerosis, smooth muscle cells sometimes undergo cell division and proliferate to form new intimal tissue (although smooth muscle cell proliferation is not as prominent as researchers thought 20 years ago). Even more, smooth muscle cells are stimulated to make new collagen. These actions together might be termed "fibroproliferation." Fibroproliferation is both good and bad. As the dead, cholesterol-filled core of the atherosclerotic plaque begins to grow deep in the arterial intima, the smooth muscle cells near the surface begin to undergo fibroproliferation. They form the "fibrous cap" of the atherosclerotic plaque, which sits between the core and the endothelial surface. A strong fibrous cap will keep the plaque from rupturing and thus will prevent a heart attack. In this case, fibroproliferation is a good thing.
On the other hand, excessive fibroproliferation can begin to choke off the flow of blood in the artery. Most atherosclerotic plaques in the coronary arteries responsible for coronary chest pain have blocked 70% or more of the area through which blood ordinarily flows - this is called 70% or greater stenosis. In these plaques, excessive collagen usually accounts for the bulk of obstructing intimal tissue. Therefore, researchers have often tried to find ways to prevent fibroproliferation of smooth muscle cells. But this would have the effect of weakening the fibrous cap, perhaps leading to more heart attacks. It is a difficult balancing act. A better strategy may be to prevent, slow, or reverse the development of the cholesterol-rich core, which precedes fibroproliferation in atherosclerotic lesion development.
John R. Guyton, MD