Hyaluronic acid: targeting immune modulatory components of the extracellular matrix in atherosclerosis

Atherosclerosis is a chronic inflammatory disease of the vessel wall. Although it has become common knowledge that hyaluronic acid (HA), an important component of the extracellular matrix, is strongly involved in atherosclerotic disease development it has only recently become evident that HA, instead of being a static matrix polymer, is an active modulator of proliferation and inflammation of the atherosclerotic plaque. This review discusses the regulatory capacity of HA in atherosclerotic lesions and its effects on plaque stability.

The mechanisms by which HA might alter plaque stability are diverse. It regulates cellular migration and proliferation, lipid accumulation, and intraplaque angiogenesis. Smooth muscle cell migration is enhanced upon accumulation of HA, potentially stabilizing atherosclerotic plaques. On the other hand, HA is an important ligand for CD44, which stimulates inflammatory cell recruitment to lesions, leukocyte migration and cell proliferation in atherosclerotic plaques. Furthermore, HA forms complexes with low density lipoproteins, and uptake of these complexes by macrophages is increased compared to native LDL, indicating a more detrimental effect on atherosclerosis. The dynamic functional role of HA might be based on the functional difference between short and larger size fragments of this polymer, with either an inflammatory or an anti-inflammatory besides a pro-mitogenic and anti-mitogenic effect. Low molecular weight HA has been shown to be pro-angiogenic, whereas high molecular weight HA has an anti-angiogenic effect. The cause of these differential actions might be that HA synthesis is regulated by three different genes: HAS1, 2 and 3 leading to different size HA products. These genes are specifically expressed under certain conditions, e.g. HAS1 and HAS3 are selectively induced in inflammation, suggesting an important role of their products in this process.

Hyaluronic acid is an active regulatory component of atherosclerotic lesions. Further studies are warranted to gain more insight into the mechanisms which decide on the role of HA in atherosclerosis and plaque stability.