Overexpression of hyaluronan in the tunica media promotes the development of atherosclerosis

The arterial content of hyaluronan (HA) undergoes diffuse changes as part of the diabetic macroangiopathy. Because HA influences the phenotype of vascular cells in vitro such as proliferation, migration, and secretion, it is tempting to speculate that diabetes-induced hastened cardiovascular disease may be linked to the increased amount of HA. To explore the pathophysiological role of altered HA content in the arterial wall in vivo, we created transgenic (Tg) mice with HA overexpression in smooth muscle cells (SMCs) in large and small vessels, targeted by the alpha smooth-muscle-cell-actin (alpha SMA) promoter fused to the human hyaluronan synthase 2 (hHAS2) cDNA. RT-PCR demonstrated hHAS2 mRNA expression in the tunica media of large and small vessels. In situ hybridization confirmed that hHAS2 mRNA was targeted to the SMCs. The aortic HA content was elevated in the Tg mice, and by immunohistochemistry, it was seen that HA accumulated in the tunica media. The secretory profile of high- and low-molecular HA was similar in wild-type and Tg animals. Overproduction of HA in the aorta resulted in thinning of the elastic lamellae in Tg mice. Our data suggest that this may lead to increased mechanical stiffness and strength, as determined by controlled stretching until failure. Finally, overproduction of HA on the genetic background of the ApoE-deficient mouse strain promoted atherosclerosis development in the aorta. These results indicate that a single component of the diabetic macroangiopathy, diffuse accumulation of HA, accelerates the progression of atherosclerosis.