Endothelial cells are the inner lining cells of arteries and all blood vessels. The endothelium is a term that just means all the endothelial cells. These cells are long, wide, and very flattened, as is appropriate for lining cells. They are arranged like paving stones on the inner surface of the arterial wall. Endothelial cells are joined at their edges, forming a seal that is almost water-tight. Cells in the flowing blood never come into contact with the underlying connective tissue of the arterial intima, as long as the endothelial surface is intact.
Over the past century and especially in recent decades, researchers have discovered a number of interesting things about endothelial cells. Early on, it was recognized that endothelial cells are unusual in that blood does not clot when in contact with endothelial cells. Blood does clot when it contacts most of the other cell types in the body. The endothelial cell surface resists clotting. In addition, endothelial cells release certain chemicals that inhibit clotting of blood platelets (clotting cells in the blood).
There is a tendency to think that people with atherosclerosis may do better if their endothelial cells very actively resist clotting. That might be the case. However, since most heart attacks result from clots at the site of big, gaping holes in ruptured atherosclerotic plaques, the potential effectiveness of promoting endothelial cell resistance to clotting is unproven.
Endothelial cells not only form a barrier between blood cells and underlying tissue, but also form a barrier between most of the proteins in the blood and the underlying tissue. In particular, this is true for low density lipoproteins (LDL). Because the endothelial cells are an effective barrier for passage of LDL, we used to think that LDL levels in the arterial intima will remain low as long as the endothelial surface is intact. That turns out not to be the case, as explained earlier ("Low density lipoproteins in the arterial intima"). LDL levels in the arterial intima are approximately equal to plasma levels. Nevertheless, because of the endothelial barrier to passage of LDL, the movement of LDL across the endothelium is very slow in both directions (into and out of the intima), and individual LDL particles remain in the intima for very long periods of time.
One of the most fascinating things about endothelial cells is their role in determining the diameter to which arteries will grow. In the 1930s it was observed, by making windows in eggs to look through a microscope at developing chicken embryos, that tiny arteries with a lot of blood flow would grow, while those with sluggish or no blood flow would wither away. It has since been proven that the rate of blood flow determines the size to which an artery will grow. This even occurs in adult animals. If a leg is cut off in an accident, then the artery supplying the stump will wither down to a small size. On the other hand, when a surgeon creates a fistula, that is, a direct artery-to-vein connection, in the forearm of a kidney dialysis patient, then the artery supplying the fistula will actually grow in diameter over a number of months. This is due to the very high rate of blood flow in the fistula and its supplying artery.
If the Alaska pipeline could have been made of material as smart as human arteries, then the pipeline company might have laid down only a quarter inch pipe along the entire distance, and the pipe would have grown to an appropriate size and thickness to support thousands of gallons of oil per hour.
How does an artery grow to a certain size depending on its blood flow? The endothelial cells are able to detect the rate of blood flow across their surface. The signal probably starts near the cell surface membrane, where a tethering filament inside the cell binds to the membrane. The frictional force of blood flowing past the cell membrane will be concentrated at the end of the tethering filament. This appears to open a molecular gate for calcium ions to enter the endothelial cell. Increasing the calcium level inside the cell causes it to start making signaling molecules that are shipped out the lower surface of the endothelial cell. Smooth muscle cells in the arterial wall, both intima and media, relax in response to the signaling molecules. As the smooth muscle cells relax, the artery dilates (widens) just a little bit. The diameter of the artery increases about 5 to 15 percent. This is not much, but it is enough to put the collagen and elastin fibers in the artery wall under considerable tension. Over the course of months the collagen and elastin fibers eventually relax or remodel, allowing the artery diameter eventually to increase as much as 100 percent or more in some circumstances.
It's important to note that when the artery diameter increases, the speed, or velocity, of blood flow slows down. A big pipe can deliver the same amount of blood at a lower velocity than a small pipe. Think about a river. The amount of water flowing down the river is approximately the same for many miles. At wide parts of the river, the flow is slow. At narrow places, the flow is rapid as the water squeezes through the narrow or shallow spots. The same thing happens in blood vessels. After the artery grows, the endothelial cells will detect a reduced, more normal flow velocity that "they are more pleased with." The endothelial cells then turn off the relaxation signaling molecules, and the artery diameter stops growing.
In the early 1980s a blood vessel biologist made the discovery that endothelial cells can send a relaxation signal to smooth muscle cells. It took several more years before the signal was identified as an astonishingly simple molecule, nitric oxide, composed of one atom of nitrogen and one atom of oxygen. Pure nitric oxide is a gas, but in the body, nitric oxide is dissolved in body fluids. Nitric oxide is a highly reactive and unstable molecule. Once it is formed, it remains as nitric oxide for only six seconds in body fluids. The smooth muscle relaxation system to nitric oxide is the same system that responds to nitroglycerin, which coronary patients take to relieve anginal chest pain. In the penis, the same system responds to Viagra to produce an erection. (This helps explain why a patient who takes nitroglycerin within 24 hours after taking Viagra can suffer fatal loss of blood pressure.) Nitric oxide is actually made by many different types of cells in the body; it plays a role in inflammation, lung function, and brain function. Over the past 2 decades, nitric oxide has gathered a glittering scientific resumé, somewhat like that of cholesterol!
People at risk for coronary heart disease and stroke (most of us, actually) can make use of the endothelial cell/nitric oxide/smooth muscle relaxation system to improve the long-term clinical outlook. We can rev up nitric oxide production in the coronary arteries simply by exercising. Aerobic exercise is required. When air is moving rapidly in and out of the lungs, the heart is also pumping blood rapidly around the body, and the heart itself is receiving increased rates of blood through the coronary arteries. If blood flows rapidly through the coronary arteries, the result is increased nitric oxide production by the coronary endothelial cells. The coronary arteries actually enlarge a little bit as they relax. In animal studies, exercise has produced long-term, structural enlargement of the coronary arteries. If atherosclerotic plaques are developing, then there is more room for them in enlarged coronary arteries! Furthermore, nitric oxide hinders clotting of blood platelets, and it also seems to inhibit atherosclerosis development in ways that are not yet clear. It has been estimated that moderate aerobic exercise (about 2 to 3 hours per week at levels that just noticeably increase breathing, but do not cause breathlessness) may lower the long-term risk of coronary disease by half! Most of the benefit of exercise may occur as blood flows faster through the coronary arteries, turning on the production of nitric oxide by endothelial cells.
There is yet another aspect to the endothelial cell/nitric oxide/smooth muscle relaxation system that will help us to understand atherosclerosis better. The nitric oxide response to blood flow velocity helps arteries to resist the formation of blockages that cause anginal chest pain. Here is how it happens: When an atherosclerotic plaque develops and an artery just begins to pinch a little tighter, the blood flow speeds up at the site of the plaque, just as water flow speeds up at a narrow spot in a river. But an increase in blood flow velocity will cause endothelial cells at the site to make more nitric oxide and lead to relaxation and enlargement of the artery. The diameter of the channel for blood flow tends to remain unchanged. The artery, therefore, bulges outward, not inward, at the site of an early atherosclerotic plaque. Only advanced atherosclerotic plaques actually lead to inward bulging and pinching off of arterial blood flow. Unfortunately, this means that by the time that a patient actually feels anginal chest pain or has an abnormal exercise stress test due to arterial blockage, coronary atherosclerosis is already far advanced.
The endothelial cell/nitric oxide/smooth muscle relaxation system works a little differently in every person. The capacity of this system to widen the coronary arteries or an artery in the arm can be measured using research techniques. Recently researchers have found that an active arterial relaxation system predicts good outcomes in clinical coronary heart disease. Differences between people in the activity of this system are thought to be partly inherited and partly due to clinical factors. One of the strongest clinical factors is, in fact, an old enemy - high LDL cholesterol. Reducing LDL cholesterol makes arteries relax and widen more effectively.
Nitric oxide production represents the good side of endothelial cell activity in the arterial wall. Endothelial cells, however, can also play a bad role in recruiting inflammatory cells from the blood into the arterial intima. When they are stimulated by pro-inflammatory factors, endothelial cells begin to display "adhesion molecules" on their surface that attach to and bind blood monocytes and lymphocytes (these are the key inflammatory cells recruited from the blood in atherosclerosis). After monocytes and lymphocytes become firmly attached, they squeeze through tight gaps between the endothelial cells to enter the arterial intima. Within the intima, both monocytes and lymphocytes become activated to carry out inflammatory functions. As discussed earlier, inflammation is part of the atherosclerotic process. One way to reduce inflammation may be to inhibit the initial endothelial expression of adhesion molecules.
John R. Guyton, MD