Lipoprotein retention in the vascular wall – a potential therapeutic target?

Extracellular matrix in the vascular wall

In normal arteries, much of the extracellular matrix (up to 50 %) consists of elastic fibre proteins, collagen and smaller amounts of proteoglycans (6). As lesions develop in the vascular wall, the ratio of these components gradually changes. In the early stages, the amount of proteoglycans increases sharply, while elastic fibres and collagen become less abundant. In the later stages, however, the amount of collagen increases, while elastic fibres and proteoglycans are reduced. Matrix components are also found in the glycocalyx layer (7), which coats the surface of the vascular wall facing the bloodstream. The role of the glycocalyx in the development of atherosclerosis has been little studied to date.

The various components of the extracellular matrix have different structures, properties and functions in the vascular wall. Changes in their relative abundance will affect the functions of the individual components and of the vascular wall in general, especially in vulnerable areas such as the aorta, coronary vessels and cerebral arteries. The thickening of the intimal layer of the vascular wall results both from an increase in the number of smooth muscle cells as well as an increase in the extracellular matrix produced by those cells. A key factor contributing to the increased vessel stiffness (6) seen with more advanced atherosclerosis is the accumulation of extracellular matrix and of cross-links between matrix components. These cross-links make the matrix more resistant to enzymes that are usually responsible for the dynamic turnover of connective tissue in vascular walls (8).

Atherosclerosis is the underlying cause of 80–85 % of all cardiovascular disease

Proteoglycans are a key component of the extracellular matrix in the vascular wall and are of great importance for the development of atherosclerosis. Proteoglycans are proteins with highly negatively charged polysaccharide chains known as glycosaminoglycans (9). These chains contribute to the binding of water that generates the hydrated and flexible matrix structures seen in tissues exposed to high pressures, such as in arterial trees and in cartilage, including in knee joints. In addition, proteoglycans bind low density lipoprotein (LDL) and very low density lipoprotein (VLDL) as well as a number of proteins and apoproteins that are important in lipoprotein turnover and function, as shown in Table 1. The strongest binding is usually seen with heparan sulphate, primarily due to its high charge density, but also because of specific structures in its glycosaminoglycan chains. In the case of apolipoprotein B (apoB), a defined part of the protein binds to glycosaminoglycans, namely regions that are exposed on the surface of the protein and that contain short sequences of basic and positively charged amino acids. Proteoglycans are therefore important in normal lipoprotein turnover, in part through binding lipoproteins via apoB or apoE in association with lipoprotein receptors (10).

The quantity of proteoglycans increases upon development of atherosclerosis, especially in the initial phase. Through the use of advanced extraction methods and structural studies, it has been possible to identify the proteoglycans that accumulate in atherosclerotic plaques. The small leucine-rich proteoglycans biglycan and decorin (11) have received much attention because they bind to collagens. Versican and perlecan are other important proteoglycans implicated in these processes.