Role of hyaluronan in atherosclerosis: Current knowledge and open questions.

Hyaluronan (HA), HA synthases (HAS) and HA receptors are expressed during the progression of atherosclerotic plaques. HA is thought to promote the activated phenotype of local vascular smooth muscle cells characterized by increased migration, proliferation and matrix synthesis. Furthermore, HA may modulate the immune response by increasing macrophage retention and by promoting the polarization of Th1 cells that enhance macrophage driven inflammation as well. The pro-atherosclerotic functions of HA are opposed by the presence of HA in the glycocalyx where it critically contributes to anti-thrombotic and anti-inflammatory function of the glycocalyx. Patients with atherosclerosis often are affected by comorbidities among them diabetes mellitus type 2 and inflammatory comorbidities. Diabetes mellitus type 2 likely has close interrelations to HA synthesis in atherosclerosis because the activity and transcription of HA synthases are sensitive to the intracellular glucose metabolism, which determines the substrate availability and the posttranslational modifications of HA synthases. The pro-inflammatory comorbidities aggravate the course of atherosclerosis and will affect the expression of the genes related to HA biosynthesis, -degradation, HA-matrix assembly or signaling. One example being the induction of HAS3 by interleukin-1β and other cytokines. Furthermore complications of atherosclerosis such as the healing after myocardial infarction also involve HA responses.