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Review
, 71-72, 396-420

A Role for Proteoglycans in Vascular Disease

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Review

A Role for Proteoglycans in Vascular Disease

Thomas N Wight. Matrix Biol.

Abstract

The content of proteoglycans (PGs) is low in the extracellular matrix (ECM) of vascular tissue, but increases dramatically in all phases of vascular disease. Early studies demonstrated that glycosaminoglycans (GAGs) including chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS) and heparan sulfate (HS) accumulate in vascular lesions in both humans and in animal models in areas of the vasculature that are susceptible to disease initiation (such as at branch points) and are frequently coincident with lipid deposits. Later studies showed the GAGs were covalently attached to specific types of core proteins that accumulate in vascular lesions. These molecules include versican (CSPG), biglycan and decorin (DS/CSPGs), lumican and fibromodulin (KSPGs) and perlecan (HSPG), although other types of PGs are present, but in lesser quantities. While the overall molecular design of these macromolecules is similar, there is tremendous structural diversity among the different PG families creating multiple forms that have selective roles in critical events that form the basis of vascular disease. PGs interact with a variety of different molecules involved in disease pathogenesis. For example, PGs bind and trap serum components that accumulate in vascular lesions such as lipoproteins, amyloid, calcium, and clotting factors. PGs interact with other ECM components and regulate, in part, ECM assembly and turnover. PGs interact with cells within the lesion and alter the phenotypes of both resident cells and cells that invade the lesion from the circulation. A number of therapeutic strategies have been developed to target specific PGs involved in key pathways that promote vascular disease. This review will provide a historical perspective of this field of research and then highlight some of the evidence that defines the involvement of PGs and their roles in the pathogenesis of vascular disease.

Keywords: Biglycan; Decorin; Fibromodulin; Lumican; Perlecan; Vascular disease; Versican.

Figures

Figure 1
Figure 1
Composition of the extracellular matrix in atherosclerosis. Proteoglycans occupy a small percentage of the total extracellular matrix in a normal blood vessel (4%), but increase dramatically in the early lesion phase (∼50%) with concomitant decreases in elastic fibers and collagen. As lesions become more advanced (late lesion), collagen predominates with continued decreases in elastic fibers.
Figure 2
Figure 2
(A, B) Representative histologic sections of human coronary arteries showing pathological intimal thickening with macrophages stained for versican (brown). Sections kindly provided by Drs. Frank Kolodgie and Renu Virmani, CV Path Institute, Inc., Gaithersburg, MD [15]. (C, D) Sections from a human temporal pseudoaneurysm stained with a modified Movat's stain (C) which shows breaks in the intimal elastic membrane (purple) and an enrichment of proteoglycans (blue) contributing to lesion formation. Note the large number of microvessels within the adventitia and at the base of the forming lesion. (D) Immunostaining for versican of the adjacent section shows substantial involvement of this proteoglycan (black) [46]. (E, F) Histologic section of an atherosclerotic lesion immunostained for versican from an Athsq1 Homozygote mouse fed a Western-style (high fat) diet. Intense versican staining (dark brown) is seen in the media of the aortic root lesion with some positive staining seen associated with the macrophage. Adjacent western blot shows enrichment of the versican (V0, V1) protein in the lesions in the congenic strain. (F) A higher magnification of the congenic strain lesion showing intense versican staining (brown) around the macrophages that had accumulated within the lesion [128]. Sections kindly provided by Dr. Carrie L. Welch, Columbia University Medical Center, New York, NY. Magnification: A and B, ×40; C, D, and E, ×100; F, ×300.
Figure 3
Figure 3
Impact of V3 versican expression on experimental lesion formation in balloon-injured carotied arteries from New Zealand white rabbits placed on a high-fat diet. Controlled expression of V3 with the injured carotid arteries causes increased elastic fiber formation and decreased accumulation of lipid, macrophages, and versican. Sections kindly provided by Dr. Mervyn J. Merrilees, Faculty of Medical and Health Sciences, University of Auckland, New Zealand. Magnification: ×80.
Figure 4
Figure 4
Colocalization of ADAMTS4 and biglycan in podosome-like structures formed by tubulogenic HUVECs cultured in 3-dimensional (3D) collagen gels. Panels A-C are generated from whole-mounts stained by immunocytochemistry and viewed by confocal microscopy. (A) Portion of a multicellular tube. Lumen (asterisks) and cell nuclei (N) are indicated. Rosettes and plaques (arrows) appear yellow, indicating colocalization of ADAMTS4 (red) and biglycan (green) in these structures. (B) En face detail of clustered ADAMTS4 (red), biglycan (blue), and the podosome component cortactin (green) in a HUVEC shows colocalization of: yellow – cortactin with ADAMTS4; cyan – cortactin with biglycan; magenta – ADAMTS4 with biglycan; white – all three molecules. (C) Z-stack of an area similar to “B” rendered in 3D and rotated 90° as a “side view” (arrow points toward the abluminal side of the cell). The image is digitally sectioned to reveal the central location of cortactin (e.g., white area, arrowhead) within an area of colocalized ADAMTS4 and biglycan (magenta). Scale bars = 10 μm (A), 5 μm (B), and 1 μm (C).
Figure 5
Figure 5
Some of the key pathways involved in vascular lesion formation that are impacted by proteoglycans.

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