Subendothelial space

Fig. 2.1 Sequence of events in atherogenesis and role of low-density lipoprotein. Native LDL, in the subendothelial space, undergoes progressive oxidation (mmLDL) and activates the expression of MCP-1 and M-CSF in the endothelium (EC). MCP-1 and M-CSF promote the entry and maturation of monocytes to macrophages, which further oxidise LDL (oxLDL). Ox-LDL is specifically recognised by the scavenger receptor of macrophages and, once internalised, formation of foam cells occurs. Both mmLDL and oxLDL induce endothelial dysfunction, associated with changes of the adhesiveness to leukoc)des or platelets and to wall permeability.

The normal arterial wall consists of the intima, media, and adventitia, as illustrated in Fig. 4—3A. The endothelium is located in the intima and consists of a layer of endothelial cells that line the lumen of the artery and form a selective barrier between the vessel wall and blood contents. The internal elastic lamina separates the intima and media, where vascular smooth muscle cells are found. The vascular adventitia comprises the artery s outer layer. Atherosclerotic lesions form in the subendothelial space between the endothelial cells and internal elastic lamina. 

Lipid-laden macrophages, smooth muscle cells, and necrotic debris from the death of foam cells accumulate in the subendothelial space, leading to enlargement of the fatty streak. A collagen matrix forms a fibrous cap that covers the lipid core of the lesion to establish a fibrous plaque called an atherosclerotic plaque. Initially, the diameter of the coronary artery lumen is... 

Oxidized LDL are considered to be one of the major factors associated with the development of atherosclerosis. The earliest event is the transport of LDL into the arterial wall where LDL, being trapped in subendothelial space, are oxidized by oxygen radicals produced by endothelial and arterial smooth muscle cells. The oxidation of LDL in the arterial wall is affected by various factors including hemodynamic forces such as shear stress and stretch force. Thus, it has been shown [177] that stress force imposed on vascular smooth muscle cells incubated with native LDL increased the MDA formation by about 150% concomitantly with the enhancement of superoxide production. It was suggested that oxidation was initiated by NADPH oxidase-produced superoxide and depended on the presence of metal ions. 

Atherosclerotic lesions are thought to arise from transport and retention of plasma LDL through the endothelial cell layer into the extracellular matrix of the subendothelial space. Once in the artery wall, LDL is chemically modified through oxidation and nonenzymatic glycation. Mildly oxidized LDL then recruits monocytes into the artery wall. These monocytes then become transformed into macrophages that accelerate LDL oxidation. 

Even during the first or second decade of life, small deposits of lipid, fatty streaks, are often detectable in arterial walls. In a study by R. Ross over half of the children (age 10-14) examined at autopsy had fatty streaks in their arteries. These are the first indications of the entry of fat and cholesterol into macrophages in the subendothelial space of an artery. This initiates a sequence of processes that eventually produces a plaque. A prerequisite for the development of fatty streaks, and hence atherosclerosis, is injury to the endothelial cells fining the arterial wall. Many factors are suspected of causing this, including pollutants. 

A central event in the generation of plaque is the uptake of low density lipoproteins (LDL) by macrophages in the subendothelial space. LDL enters this space through the damaged endothelial cells. The uptake occurs via endocy-tosis, after the binding of LDL to one of three receptors on the macrophage ... 

Figure 22.2 Injury to endothelial cells, adhesion of monocytes and entry into subendothelial space. Injury to the cells by various factors activates genes for expression of adhesion molecules on the luminal surface of the cells. Monocytes attach to these molecules and then enter the subendothelial space. Here they are activated to form macrophages.

One role of high density lipoprotein (HDL) is to collect unesterified cholesterol from cells, including endothelial cells of the artery walls, and return it to the liver where it can not only inhibit cholesterol synthesis but also provide the precursor for bile acid formation. The process is known as reverse cholesterol transfer and its overall effect is to lower the amount of cholesterol in cells and in the blood. Even an excessive intracellular level of cholesterol can be lowered by this reverse transfer process (Figure 22.10). Unfortunately, the level of HDL in the subendothelial space of the arteries is very low, so that this safety valve is not available and all the cholesterol in this space is taken up by the macrophage to form cholesteryl ester. This is then locked within the macrophage (i.e. not available to HDL) and causes damage and then death of the cells, as described above. 

Atherosclerosis is the progressive accumulation of cholesterol, inflammatoiy and other cells, and extracellular matrix in the subendothelial space (intima) of an artery wall, ultimately leading to the formation of a plaque that can occlude the lumen (see Figure 18-19). 

There is extensive evidence that accumulation and subsequent oxidative modification of LDL particles in the subendothelial space play a key role in development and progression of atherosclerosis (Lusis 2000 Berliner et al. 1995 Leitinger 2005). Phospholipid oxidation products are found at high concentrations within fatty streak lesions of cholesterol fed rabbits, mice, and in human atherosclerotic lesions (Watson et al. 1997 Berliner et al. 2001 Subbanagounder et al. 2000 Subbanagounder et al. 2000 Huber et al. 2002). Antibodies against OxPL are present in the serum of apoE-deficient mice and the presence of antibodies against OxPL in patients with atherosclerosis, diabetes, hypertension and other chronic inflammatory diseases further underlines the importance and potential functional relevance of these molecules (Binder et al. 2005). 

The adhesion of monocytes to the vascular endothelium, followed by their recruitment into the subendothelial space, is one of the earliest events to occur in the pathogenesis of atherosclerosis and leads to the development of the lipid-laden foam cell-containing lesion (for a review see Sanders,... 

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