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Chapter 6: MOLECULAR AND CELLULAR BIOLOGY OF BLOOD VESSELS PHYSIOLOGY OF THE ENDOTHELIAL CELL

Normal endothelial cell function is crucial to homeostasis in the vascular system. During the past decade, it has become apparent that diseases such as atherosclerosis are ultimately manifestations of endothelial dysfunction. The endothelium has three major functions: (1) it is a metabolically active secretory tissue; (2) it serves as an anticoagulant, antithrombotic surface; and (3) it provides a barrier to the indiscriminant passage of blood constituents into the arterial wall. The implications of these physiologic properties for vascular biology will be considered separately.

Endothelial Cell Metabolism and Secretion of Vasoactive Factors

As discussed in more detail below, endothelial cells secrete vasoactive substances that play a major role in the control of vascular tone. These molecules include vasodilators such as prostacyclin, endothelial-derived relaxing factor (EDRF), and endothelial-derived hyperpolarizing factor (EDHF).13 In addition, the endothelium produces vasoconstrictor substances, including endothelin4 and vasoconstrictor prostanoids.5

Endothelial cells also manufacture and secrete substances such as factor VIII antigen, von Willebrand's factor, tissue factor, thrombomodulin, and tissue plasminogen activator, which are all involved in coagulation/fibrinolytic pathways. Structural components of the extracellular matrix synthesized by these cells include collagen, elastin, glycosaminoglycans, and fibronectin.67 The composition of the extracellular matrix is dynamically modulated by matrix metalloproteinases, enzymes that degrade matrix protein and participate in its remodeling. These enzymes are secreted by both endothelial and smooth muscle cells.8,9 In addition, endothelial cells synthesize and secrete heparans and growth factors that regulate smooth muscle cell proliferation.10-13 Finally, endothelial cells are able to clear and metabolically alter bloodborne and locally produced substances, including plasma lipids and lipoproteins,44 adenine nucleotides and nucleosides,45 serotonin, catecholamines, bradykinin, and angiotensin I.46

Endothelial cells are involved in the metabolism of plasma lipids in several ways. Lipoprotein lipase, an enzyme that hydrolyzes triglycerides into constituent fatty acids, is bound to the endothelial cell surface by heparan sulfates.47 The interaction of this enzyme with chylomicrons or very low density lipoprotein (VLDL) particles results in the release of free fatty acids, which can then cross the subendothelial space to the underlying smooth muscle or inflammatory cells in atherosclerosis. In addition, endothelial cells possess receptors for low-density lipoprotein (LDL),48 which regulate the transport and modification of LDL. Normally, LDL receptors are downregulated because receptor processing is inhibited in the nonproliferating monolayer.48 There are, however, two other pathways for uptake of LDL. First, LDL can be transported across the endothelium by an unknown, active, receptor-independent mechanism.49 Second, modified, or oxidized LDL can be taken up by "scavenger" LDL receptors,20 the expression of which is unaffected by the growth state of the endothelial cells. These cells also have the capacity to modify LDL,24 thus enhancing its uptake and ultimately leading to an increase in cholesterol esters in the vessel wall and, importantly, facilitating LDL uptake by inflammatory cells in disease.

The Endothelial Cell and Thrombosis

Quiescent endothelial cells normally present an antithrombotic surface that resists platelet adhesion and does not activate coagulation. (For a more detailed discussion of thrombosis, see Chap. 44.) The continuity of the endothelium is essential to this function, and nonthrombogenicity has been attributed in part to the negative charge on the surface of these cells.22 Endothelial cells are, however, capable of synthesizing and secreting prothrombotic factors, especially when stimulated with cytokines or other inflammatory agents. The endothelium thus represents a functional antithrombotic-thrombolytic/thrombotic balance. Potent anticoagulants elaborated by the endothelium include prostacyclin, which inhibits platelet aggregation,23 heparin-like molecules,24 and thrombomodulin, which activates protein C.25 In addition, antithrombin III binds to the surface-bound heparin-like molecules and serves as a clearance (via internalization) molecule for thrombin, as well as a thrombin inhibitor.26 These cells also produce tissue plasminogen activator (tPA) and plasminogen activator inhibitor I (PAI-I), and can bind plasminogen on their surface via fibronectin and thrombospondin.27 The relative amounts of tPA and PAI-I can be upregulated or downregulated, respectively, by thrombin, angiotensin II, and other vasoactive substances to control clot lysis.28

As alluded to earlier, the endothelium, under conditions of injury or inflammation, may become prothrombotic (Q+ Fig. 6-1). On stimulation with inflammatory cytokines, endothelial cells increase the surface expression of tissue factor29 and leukocyte adhesion molecules,30 and decrease the expression of thrombomodulin.29 Thrombin itself stimulates further production of von Willebrand's factor,34 which, along with thrombospondin and fibronectin, participates in the thrombotic response. Furthermore, endothelial cells can bind factor IX,32 which, when tissue factor is expressed, can be activated by tissue factor VIIa complex, leading to activation of factor X in the presence of factor VIII. Activated factor X (Xa) can then promote assembly of the prothrombinase complex. Thus, under inflammatory conditions, endothelial cells can amplify the prothrombotic response. Not all of the factors controlling the expression of pro- and antithrombotic/fibrinolytic molecules are known, but it is clear that the endothelium functions as a major regulator of hemostasis.

Barrier Function and Endothelial Cell Permeability

There are three ways that the endothelium regulates influx of macromolecules into the arterial wall: intercellular tight junctions, vesicles and/or transendothelial channels, and the lipid phase of the endothelial membrane. These pathways enable the intact endothelium to serve as a barrier, preventing or impeding highly mitogenic, thrombotic, or vasoactive substances from coming into direct contact with the underlying vascular smooth muscle. Each route has both active and passive components, and the extent to which they are utilized depends to a certain degree on the location of the endothelial cells. Thus, capillaries and postcapillary venules respond to vasoactive agents, some of which (histamine, prostaglandins) are secreted by the endothelial cell itself, with increased flux through tight junctions.33 The tight junctions found in arteries tend to be more occlusive, but may also be influenced by hypertension34 and various agonists. Vesicular transport is mainly utilized by the cell to transfer water-soluble macromolecules from the luminal surface to the abluminal surface, but the permanence of such structures and whether they form transendothelial channels is a matter of debate. It has recently been shown that caveolae, vesicles containing the structural protein caveolin that are pinched off from the plasma membrane, are involved in transendothelial transport of macromolecules. Multiple such vesicles may link together to form functional pores from the luminal to abluminal surface.35,36 Lipid-phase transport has been proposed as a mechanism whereby lipid-soluble molecules (e.g., free fatty acids) could be transferred to the abluminal surface of the endothelial cell.37 These molecules could enter the outer leaflet of the membrane from the circulation and diffuse along the lipid bilayer to be released or bind to extracellular matrix components in the subintimal area.

Another major mechanism modulating endothelial barrier formation occurs via contraction of these cells in a fashion analogous to smooth muscle contraction. This occurs in response to a variety of agonists, including thrombin, histamine, and ionomycin, and results in cell shape change that opens gap junctions between cells. It is likely that this contractile response is a major mechanism for edema formation in response to histamine and bradykinin and is also involved in solute transport. This phenomenon is mediated by a series of intracellular signaling events, including activation of protein kinase C, myosin light chain phosphorylation, activation of tyrosine kinases, and stimulation of the small G-protein Rho.38-40

Thus, the endothelium has both passive and active roles in the control of vascular permeability by acting as a physical permeability barrier and by modulating the expression of cell surface and secreted agonists and molecules that are capable of altering permeability.

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