Elaboration of Anticoagulant, Antithrombotic, Fibrinolytic Regulators

Prostacyclin

Thrombomodulin

Heparin-like molecules

Plasminogen activator

Elaboration of Prothrombotic Molecules

Von Willebrand factor

Tissue factor

Plasminogen activator inhibitor

Extracellular Matrix Production (collagen, proteoglycans)

Modulation of Blood Flow and Vascular Reactivity

Vasconstrictors: endothelin, ACE

Vasodilators: NO, prostacyclin

Regulation of Inflammation and Immunity

IL-1, IL-6, chemokines

Adhesion molecules: VCAM-1, ICAM, E-selectin P-selectin

Histocompatibility antigens

Regulation of Cell Growth

Growth stimulators: PDGF, CSF, FGF

Growth inhibitors: heparin, TGF-b

Oxidation of LDL

ACE, angiotensin converting enzyme; NO, nitric oxide; IL, interleukin; PDGF, platelet-derived growth factor; CSF, colony-stimulating factor; FGF, fibroblast growth factor; TGF-b,

transforming growth factor-beta; LDL, low-density lipoprotein.

Structurally intact ECs can respond to various pathophysiologic stimuli by adjusting their usual (constitutive) functions and by expressing newly acquired (inducible) properties—a process

termed endothelial activation ( Fig. 11-2 ). [4] [5] Inducers of endothelial activation include cytokines and bacterial products, which cause inflammation and septic shock ( Chapter 2 );

hemodynamic stresses and lipid products, critical to the pathogenesis of atherosclerosis (see later); advanced glycosylation end products (important in diabetes, Chapter 24 ), as well as

viruses, complement components, and hypoxia. Activated ECs, in turn, express adhesion molecules ( Chapter 2 ), and produce other cytokines and chemokines, growth factors, vasoactive

molecules that result either in vasoconstriction or in vasodilation, major histocompatibility complex molecules, procoagulant and anticoagulant moieties, and a variety of other biologically

active products. ECs influence the vasoreactivity of the underlying smooth muscle cells through the production of both relaxing factors (e.g., nitric oxide [NO]) and contracting factors (e.

g., endothelin). Normal endothelial function is characterized by a balance of these factors and the ability of the vessel to respond appropriately to various pharmacologic stimuli (e.g.,

vasorelaxation in response to acetylcholine).

Endothelial dysfunction, as defined by an altered phenotype that impairs vasoreactivity or induces a surface that is thrombogenic or abnormally adhesive to inflammatory cells, is

responsible, at least in part, for the initiation of thrombus formation,

Figure 11-2Endothelial cell response to environmental stimuli: causes (activators) and consequences (induced genes).

Figure 11-3Schematic diagram of the mechanism of intimal thickening, emphasizing smooth muscle cell migration to, and proliferation and extracellular matrix elaboration in, the intima.

(Modified and redrawn from Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, W.B. Saunders Co., 1989, p.

254.)

Figure 11-4American Heart Association classification of human atherosclerotic lesions from the fatty dot (type I) to the complicated type VI lesion. The diagram also includes growth

mechanisms and clinical correlations. (Modified from Stary HC, et al: A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis.

Circulation 92:1355, 1995.)

Figure 11-5Schematic summary of the natural history, morphologic features, main pathogenetic events, and clinical complications of atherosclerosis in the coronary arteries.

Figure 11-6Fatty streak—a collection of foam cells in the intima. A, Aorta with fatty streaks (arrows), associated largely with the ostia of branch vessels. B, Close-up photograph of fatty

streaks from aorta of experimental hypercholesterolemic rabbit shown following staining with Sudan red, a lipid-soluble dye, again illustrating the relationship of lesions to branch vessel

ostia. C, Photomicrograph of fatty streak in experimental hypercholesterolemic rabbit, demonstrating intimal, macrophage-derived foam cells (arrow). (B and C, Courtesy of Myron I.

Cybulsky, M.D., University of Toronto, Canada).

Figure 11-7Schematic depiction of the major components of well-developed intimal atheromatous plaque overlying an intact media.

Figure 11-8Gross views of atherosclerosis in the aorta. A, Mild atherosclerosis composed of fibrous plaques, one of which is denoted by the arrow. B, Severe disease with diffuse and

complicated lesions.

Figure 11-9Histologic features of atheromatous plaque in the coronary artery. A, Overall architecture demonstrating fibrous cap (F) and a central necrotic (largely lipid) core (C). The

lumen (L) has been moderately narrowed. Note that a segment of the wall is plaque free (arrow). In this section, collagen has been stained blue (Masson's trichrome stain). B, Higher-power

photograph of a section of the plaque shown in A, stained for elastin (black), demonstrating that the internal and external elastic membranes are destroyed and the media of the artery is

thinned under the most advanced plaque (arrow). C, Higher-magnification photomicrograph at the junction of the fibrous cap and core, showing scattered inflammatory cells, calcification

(broad arrow), and neovascularization (small arrows).

TABLE 11-2-- Risk Factors for Atherosclerosis

Date: 2016-04-22; view: 685