Aggrecan in Cardiovascular Development and Disease

Abstract

Aggrecan is a large proteoglycan that forms giant hydrated aggregates with hyaluronan in the extracellular matrix (ECM). The extraordinary resistance of these aggregates to compression explains their abundance in articular cartilage of joints where they ensure adequate load-bearing. In the brain, they provide mechanical buffering and contribute to formation of perineuronal nets, which regulate synaptic plasticity. Aggrecan is also present in cardiac jelly, developing heart valves, and blood vessels during cardiovascular development. Whereas aggrecan is essential for skeletal development, its function in the developing cardiovascular system remains to be fully elucidated. An excess of aggrecan was demonstrated in cardiovascular tissues in aortic aneurysms, atherosclerosis, vascular re-stenosis after injury, and varicose veins. It is a product of vascular smooth muscle and is likely to be an important component of pericellular matrix, where its levels are regulated by proteases. Aggrecan can contribute to specific biophysical and regulatory properties of cardiovascular ECM via the diverse interactions of its domains, and its accumulation is likely to have a significant role in developmental and disease pathways. Here, the established biological functions of aggrecan, its cardiovascular associations, and potential roles in cardiovascular development and disease are discussed.

Extracellular Matrix in Calcific Aortic Valve Disease: Architecture, Dynamic and Perspectives

“…It was reported that ADAMTS5 down-regulation, above all at the aortic side of the valve, accounts for VIC activation and myofibroblast or osteoblast transdifferentiation [ 106 ]. Indeed, ADAMTS5 down-regulation determines aggrecan accumulation which, in turn, might alter VICs’ phenotype as previously reported for vascular smooth muscle cells [ 98 ].…”

“…To date, more than 40 genes encoding different PGs have been identified, which have been organized in four major classes on the basis of cellular and subcellular localization [ 96 ]. Among them, only few PGs have been investigated for a role in CAVD pathogenesis and progression [ 97 , 98 , 99 , 100 , 101 , 102 ].…”

ADAMTS proteases in cardiovascular physiology and disease

“…Moreover, through their interactions with ECM proteins, growth factors and chemokines, PGs regulate a variety of processes such as cell signalling, proliferation, migration and apoptosis [ 25 ]. Increased accumulation of PGs is a feature of atherosclerosis [ 26 , 27 ] and aneurysms [ 28 ], as well as hereditary diseases such as pediatric aortic valve disease and adult myxomatous mitral valves [ 29 ].…”

“…Plaque rupture with subsequent thrombus formation can cause vascular occlusion leading to potentially fatal cardiovascular events such as myocardial infarction and stroke. PGs such as versican and aggrecan also tend to accumulate in thoracic aortic aneurysms and dissections (TAAD) [ 28 , 30 , 31 ] and during normal ageing of the aorta [ 32 ], resulting in an increased osmotic pressure that is disruptive to the ECM ( figure 1 b ). Moreover, PG accumulation can disrupt mechanosensing by VSMCs and create stress-risers in the aortic wall that may predispose to or propagate a dissection [ 33 ].…”

“…Aggrecan, a major CSPG in cartilage, has been recently identified in human aortas [ 28 , 30 , 31 , 48 – 53 ] and, together with versican, it has been shown to accumulate in the aortas of patients with TAAD, resulting in an increased osmotic pressure that is disruptive to the ECM [ 30 ] ( figure 1 b ). Here, it is important to note that aggrecan has an order of magnitude more CS than versican [ 54 ], and therefore more potential to exert osmotic pressure.…”