Human Physiology, 14th edition (2016)

Blood, Heart, and Circulation 437

and exposes the underlying tissue to the blood, thrombi (clots)

form.

Endothelial cells normally prevent the progression just

described by presenting a physical barrier to the penetration

of monocytes and lymphocytes and by producing paracrine

regulators such as nitric oxide. The vasodilator action of nitric

oxide helps to counter the vasoconstrictor effects of another

paracrine regulator, endothelin-1, which is increased in ath-

erosclerosis. Hypertension, smoking, and high blood choles-

terol interfere with the protective function of the endothelium,

whereas regular aerobic exercise improves it.

Cholesterol and Plasma Lipoproteins

There is considerable evidence that high blood cholesterol is

associated with an increased risk of atherosclerosis. High blood

cholesterol can be produced by a diet rich in cholesterol and sat-

urated fat, or it may be the result of an inherited condition known

as familial hypercholesteremia. This condition is inherited as

a single dominant gene; individuals who inherit two of these

genes have extremely high cholesterol concentrations (regard-

less of diet) and usually suffer heart attacks during childhood.

cells. The more advanced lesions, called fibrous plaques,
consist of a cap of connective tissue with smooth muscle
cells over accumulated lipid and debris, macrophages that
have been derived from monocytes (chapter 15), and lympho-
cytes. The fibrous cap of an advanced atherosclerotic lesion
becomes thin and prone to rupture, promoting the formation
of a thrombus.
The disease process may be instigated by damage to the
endothelium, but its progression is promoted by inflamma-
tion that is stimulated by a wide variety of cytokines and other
paracrine regulators secreted by the endothelium and by the
other participating cells, including platelets, macrophages, and
lymphocytes. Some of these regulators attract monocytes and
lymphocytes to the damaged endothelium and cause them to
penetrate into the tunica interna. The monocytes then become
macrophages, engulf lipids, and take on the appearance of foam
cells. Smooth muscle cells change from a contractile state to a
“synthetic” state, in which they produce and secrete connec-
tive tissue matrix proteins. However, cytokines released during
inflammation can reduce smooth muscle collagen synthesis
and stimulate the production of collagenase enzymes in macro-
phages, weakening the plaque’s collagen cap. When it ruptures

Figure 13.31 Atherosclerosis.

( a ) A photograph of the lumen (cavity) of a human

coronary artery that is partially occluded by an

atherosclerotic plaque and a thrombus. ( b ) A diagram

of the structure of an atherosclerotic plaque that has

ruptured and induced the formation of a thrombus.

Lipid

core

Fibrous cap

rupture

Smooth

muscle

cells

Cholesterol

crystals

Macrophages Foam

cell

Collagen

Thrombus

formation

Thrombus

Plaque

(a)

(b)