Aterosklerosis

Atherosclerosis is the thickening and hardening of

the walls of arteries caused by atherosclerotic plaques

of lipids, cells, and connective tissue deposited in the

tunica intima. Atherosclerosis is frequently seen in

arteries sustaining high blood pressure, it does not

affect veins and is the cause of myocardial infarction,

stroke, and ischemic gangrene.

Atherosclerosis is a chronic inflammatory disease

driven by the accumulation of cholesterol-laden

macrophages in the artery wall. Atherosclerosis is

characterized by features of inflammation at all stages

of its development (Figure 12-15).

The atherosclerotic process is initiated when

cholesterol-containing low-density lipoproteins

(LDLs) accumulate in the intima as a consequence of

endothelial cell dysfunction. A dysfunctional endothelium

expresses vascular cell adhesion molecule-1

(VCAM-1) that enables monocytes to attach to the

endothelial cell surface, cross the endothelium and

penetrate the intima of the blood vessel.

Monocytes then differentiate into macrophages

expressing on their surface scavenger receptor-A (SRA).

SR-A uptakes a modified form of LDL (oxidized

LDL) and the massive accumulation transforms macrophages

into cholesterol-laden foam cells. Macrophage

foam cells constitute the atheroma core of the

atherosclerotic plaque. The atheroma core continues

to enlarge and smooth muscle cells of the tunica

muscularis migrate to the intima forming a collagencontaining

fibrous cap overlying the atheroma core.

The endothelium covers the fibrous cap.

The lipid core enlarges and triggers an inflamma-

Atherosclerosis

tory response attracting T cells that stimulate macrophage

foam cells to produce metalloproteinases that,

together with proinflammatory cytokines produced

by T cells, weaken the fibrous cap making it susceptible

to fracture that predisposes to thrombosis in the

presence of procoagulant tissue factor. An enlarging

thrombus will eventually obstruct or occlude the lumen

of the affected blood vessel.

As you can see, the clearance of lipoproteins by

macrophages appears initially beneficial but, with

time, the macrophage function is compromised and

starts to contribute to the inflammatory response

through the secretion of pro-inflammatory mediators

and extracellular matrix proteases. With time, dying

macrophages release their lipid contents, which leads

to the enlargement of the atheroma core.

The major blood vessels involved are the abdominal

aorta and the coronary and cerebral arteries.

Coronary arteriosclerosis causes ischemic heart

disease and myocardial infarction occurs when the

arterial lesions are complicated by thrombosis.

Atherothrombosis of the cerebral vessels is the

major cause of brain infarct, so-called stroke, one of

the most common causes of neurologic disease. Arteriosclerosis

of the abdominal aorta leads to abdominal

aortic aneurysm, a dilation that sometimes ruptures

to produce massive fatal hemorrhage.

Atherosclerosis correlates with the serum levels

of cholesterol or low-density lipoprotein (LDL). A

genetic defect in lipoprotein metabolism (familial

hyper-cholesterolemia) is associated with atherosclerosis

and myocardial infarction before patients reach

20 years of age. We discuss in Chapter 2, Epithelial

Glands, that familial hypercholesterolemia is caused

by defects in the LDL receptor, resulting in increasing

LDL circulating levels in blood. In contrast to LDL,

high-density lipoprotein (HDL) transports cholesterol

to the liver for excretion in the bile (see in the

gallbladder section of Chapter 17, Digestive Glands).