A role for proteoglycans in vascular disease

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.

Versican—A Critical Extracellular Matrix Regulator of Immunity and Inflammation

“…Interestingly, the different isoforms exhibit functional differences regarding their impact on cell phenotype, such as the ability of V1 to promote proliferation and inhibit apoptosis, while V2 exhibits antiproliferative activity (37,38). In contrast, V3 regulates ECM assembly and inhibits cell proliferation and migration (39)(40)(41)(42)(43)(44)(45). A new V5 isoform has been recently described and shown to be expressed by injured rat neurons (46).…”

“…Versican is essential during development (76,77) and it is now becoming apparent that it is an important component of the tissue inflammation caused by infection and tissue injury (10). Versican accumulates as part of the early inflammatory response in a number of human diseases often associated with the invasion of leukocytes including those in the vascular system (10,40,(78)(79)(80)(81)(82)(83)(84), lung (5,6,60,77,(85)(86)(87)(88)(89), brain and spinal cord (53,(90)(91)(92), intestine (93)(94)(95)(96), heart (97), liver (63), skin (98,99), eye (100, 101), pancreatic islets (102), and many different forms of cancer [reviewed in (103)(104)(105)]. The accumulation of versican in these tissues is usually associated with other ECM components that bind versican, such as hyaluronan (106,107), link protein, TSG-6, IαI, and CD44 (95, 96, 108-111) (Figure 1).…”

Concise Review: The Endothelial Cell Extracellular Matrix Regulates Tissue Homeostasis and Repair

“…In particular, the ability of heparan sulfate domains to mediate binding of specific proteins is fundamental to the organization of protein–receptor interactions at the cell surface and for the creation of chemotactic gradients of growth factors and chemokines . For example, heparan sulfate facilitates the interaction of growth factors, such as FGF‐2, VEGF and heparin‐binding epidermal‐like growth factor, with their respective receptors . Upon EC injury resynthesis of membrane bound glycosaminoglycans occurs where sulfation patterns, and consequently also growth factor and morphogen binding, are modified to adapt to the altered microenvironment (for review see Rabelink et al ).…”

A pivotal role for Nrf2 in endothelial detachment- implications for endothelial erosion of stenotic plaques

“…The recent observation that OCT-defined plaque erosion patients have increased HYAL2 (the enzyme responsible for degrading high-molecular-weight hyaluronan to its proinflammatory 20-kDa isoform) and the hyaluronan receptor CD44v6 adds weight to a potential causal relationship [9]. Hyaluronan and versican may regulate vascular inflammation in atherosclerosis [75,76]. Hyaluronan (and biglycan) can bind to and activate TLR2 and TLR4 [77,78].…”