Vascular proteoglycans and atherosclerosis: not over yet.

The role of proteoglycans in atherosclerosis has been under increasing study lately. Proteoglycans are a family of molecules composed of a core protein with attached glycosaminoglycan chains. As a class they are ubiquitous, although different proteoglycan species have different tissue distributions and expression patterns. In the vasculature, extracellular matrix proteoglycans, especially those in the small leucine rich repeat class, have several putative roles in atherosclerosis. Proteoglycans are thought to have a role in collagen fibrillogenesis and the organization and structure of the extracellular matrix. As such, changes in the proteoglycan composition of the matrix can affect matrix stability, elasticity, tensile strength, and other functions1. In addition to their roles in extracellular matrix organization, a number of proteoglycans have been shown to have a role in the regulation of cytokines and growth factors including TGF-β2. Thus, changes in the proteoglycan composition of the vasculature may alter the bioavailability of signaling molecules that can have pathogenic consequences. As an example, overexpression of decorin via an adenoviral vector in apoE−/− mice was shown to decrease the progression of atherosclerosis, and the authors suggested that this may be due to the reduction in circulating free TGF-β observed3. Recently, additional studies have described a role for soluble proteoglycans in the regulation of inflammation. For example biglycan, primarily in its soluble form released from matrix during tissue injury, has been shown to interact with a number of molecules including bone morphogenic proteins (BMP)-2,4,6, TGF-β, TNF-α, VEGF, and is a ligand for a number of receptors including the toll-like receptors (TLR)-2 and 4 (for review see 4). Other putative roles for proteoglycans in the vasculature include the regulation of vascular smooth muscle proliferation and migration5,6. Furthermore, as outlined in the “response to retention hypothesis” proteoglycan-mediated lipid retention is thought to be one of the initiating steps in atherosclerosis development7. Positively charged motifs on apolipoproteins B and E can ionically interact with negatively charged sulfate and carboxylic acid groups on glycosaminoglycans, leading to prolonged retention of atherogenic lipoproteins in the subendothelial space. Co-localization studies have suggested that in humans biglycan is a key proteoglycan mediating lipid retention8,9, whereas in mice both biglycan and perlecan co-localize with apolipoproteins10,11. However, the role of biglycan in atherosclerosis development is unclear: we recently demonstrated that overexpression of biglycan increased atherosclerosis, but biglycan deficiency was not protective12,13. In these studies we demonstrated increased vascular perlecan content in biglycan deficient mice suggesting a compensatory response of the vasculature for the biglycan deficiency12. However, the role of perlecan in atherosclerosis is also unclear: decreased vascular perlecan content (using a heterozygous model as the perlecan deficient mouse is not viable) was shown to have decreased early atherosclerosis, but not later atherosclerosis in the apoE−/− model, and no effect in the LDL receptor deficient model14. Thus, various proteoglycans appear to play a variety of roles in atherosclerosis development, but their effects vary and definitive proof of a critical role for proteoglycans remains elusive.