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2282 Part XII: Hemostasis and Thrombosis Chapter 134: Atherothrombosis: Disease Initiation, Progression, and Treatment 2283

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radical gas with multiple physiologic properties, including inhibition NO availability. The decreased vasodilatory capacity because of dyslip-
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of platelet aggregation and inflammation and stimulation of angiogene- idemia may facilitate the development of coronary ischemia.
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sis. Numerous studies indicate that the endothelium does not vasodilate Impaired endothelial vasodilation is noted with advanced aging,
appropriately in the setting of traditional and emerging cardiovascular when the hands are exposed acutely to cold, and during mental stress.
risk factors. Cardiovascular risk factors are thought to reduce NO avail- The impairment may be mediated by increased production of endothe-
ability through a variety of mechanisms, including increased oxidative lin, a potent vasoconstrictor. Sex differences are also seen in endothe-
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stress, through generation of reactive oxygen species, and in so doing lial function as women in middle age tend to have more endothelial
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create an environment conducive to development of atherosclerosis. vasodilation than men at any age. Proinflammatory cytokines may
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Major sources of reactive oxygen species are nicotinamide adenine induce formation of endothelial-derived EVs making them a surrogate
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dinucleotide phosphate (NADPH) oxidases (NOXs). The catalytic sub- marker for endothelial dysfunction and a biomarker for cardiovascu-
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units of the NOXs are the NOX proteins and are found in atheroscle- lar events. Infection with concomitant inflammation is associated with
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rotic lesions. A reduction in NO synthesis is thought to occur because impaired endothelial vasodilation. For example, repeated infection with
of decreased availability of tetrahydrobiopterin, an essential cofactor for Chlamydia pneumoniae results in endothelial dysfunction via impaired
synthesis of NO. Administration of sepiapterin, a substrate for tetrahy- NO availability. The combination of coronary artery disease and ele-
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drobiopterin, improves endothelial dysfunction. Also, recent evidence vated serum levels of high-sensitivity C-reactive protein (hsCRP) is an
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indicates that the transcription factor p53 and the adaptor protein Shc independent predictor of abnormal endothelial vasoreactivity. Exter-
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both play essential roles in impairing endothelium-dependent vascu- nal radiation therapy also results in endothelial dysfunction and may
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lar relaxation. High cholesterol levels are thought to produce oxygen explain the increased risk of atherosclerosis in patients receiving mantle
free radicals that may inactivate NO. NO synthases are the enzymes irradiation for Hodgkin lymphoma. 48
responsible for converting l-arginine to NO (Fig. 134–2) (Chap. 115).
The enzyme may be perturbed by modified low-density lipoprotein Endothelial Inflammation
(LDL), resulting in decreased NO production. Supplementation of the The endothelium does not routinely interact with inflammatory cells but
diet with l-arginine leads to improvement in endothelial-dependent is poised to express adhesion molecules after stimulation with inflam-
vasodilation. Elevated levels of asymmetric dimethylarginine, an matory mediators. An inflammatory response is thought to begin in the
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endogenous competitive inhibitor of NO synthase, found in patients vessel wall after “invasion” of pathogenic lipoproteins. The presence of
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with hypercholesterolemia and diabetes, also may result in decreased lipoproteins, especially oxidized LDL, results in expression of adhesion
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NO availability. Oxidized LDL is thought to increase the elaboration molecules such as vascular cell adhesion molecule (VCAM)-1 on the
of asymmetric dimethylarginine by endothelial cells and decrease its luminal surface of endothelial cells, leading to adherence of monocytes
degradation by the enzyme dimethylarginine dimethylaminohydro- (Fig. 134–3). Endothelial cell expression of adhesion molecules and
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lase. Administration of acetylcholine to patients with elevated serum accumulation of monocytes can be regarded as endothelial dysfunction
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LDL and relatively low high-density lipoprotein (HDL) may result in because these events may occur in the absence of morphologic changes
abnormal vasoconstriction, which can be reversed with nitroglycerin in the vessel wall. Inflammation may develop without the demonstrable
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(an endothelium-independent vasodilator). Intravenous infusion of presence of an external microbial pathogen. It is now recognized that
HDL improves endothelial-mediated vasodilation through improved diseases with inflammatory component such as psoriasis and systemic
lupus erythematosus (SLE) confer an increased risk for atherosclerosis
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and MI. The complex interactions of inflammation and the endothe-
sGC ↑ cGMP ↓ Platelet lium on the initiation and progression of atherosclerosis are reviewed in
aggregation more detail in “Inflammation and Atherosclerosis” below.
Platelet
Abnormal Control of Vascular Growth: Smooth Muscle Cells
eNOS
L-Arginine NO and Extracellular Matrix
Normal endothelium inhibits vascular smooth muscle cell prolifer-
Endothelium ation. The specific function of vascular smooth muscle cells in ath-
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erosclerosis is unclear. However, evidence indicates that, in early
Soluble guanylate cyclase (sGC) atherosclerosis, vascular smooth muscle cells contribute to the develop-
ment of atheroma through production of proinflammatory mediators
SMC ↑ cGMP such as CC chemokine ligand (CCL)2 (previously termed monocyte che-
moattractant protein, or MCP-1) and VCAMs. Although smooth mus-
cle cells primarily play a role in modulating vascular tone, they also are
↓ Tone ↓ Growth ↓ Migration
involved in the control of extracellular matrix formation and degrada-
Figure 134–2. Vascular tone depends on endothelial production tion through matrix modulators such as proteases, protease inhibitors,
and release of various vasoconstricting and vasodilating substances. matrix proteins, and integrins (Fig. 134–4).
The endothelial-derived vasodilators include nitric oxide (NO) and The importance of vascular smooth muscle cells in controlling the
prostacyclin. NO is generated from the amino acid l-arginine by con- synthesis of matrix molecules is evident at the clinical level. They pro-
stitutive endothelial NO synthase (eNOS, or NOSIII). The enzyme is vide a thick, fibrous cap that promotes stability and inhibits plaque rup-
stimulated by blood flow across the endothelial surface (shear stress) ture and ulceration. Factor VII–activating protease, thought to play a
or by chemical mediators, such as acetylcholine, which stimulate recep- role in coagulation and fibrinolysis, is also a potent inhibitor of vascular
tors on the endothelial surface. NO diffuses to the underlying smooth smooth muscle cell proliferation, and migration in vitro and local appli-
muscle cells (SMCs), where it stimulates guanylate cyclase to generate
cyclic guanosine V monophosphate (cGMP), which causes smooth cation of factor VII–activating protease (but not Marburg I variant)
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muscle relaxation and vasodilation. It also diffuses into blood, where it in animal models reduces neointima formation. Furthermore, it has
increases intraplatelet cGMP and thereby inhibits platelet adhesion and been localized to unstable atherosclerotic plaques and may contribute
aggregation. to plaque instability.

Kaushansky_chapter 134_p2281-2302.indd 2283 17/09/15 3:49 pm