Overexpression of Hyaluronan in the Tunica Media Promotes the Development of Atherosclerosis

Abstract

Abstract-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 ␣ smooth-muscle-cell-actin (␣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. Key Words: hyaluronan Ⅲ biomechanics Ⅲ atherosclerosis Ⅲ diabetes Ⅲ transgenic H yaluronan (HA) is a large, nonsulfated glycosaminoglycan (GAG) produced in the vasculature by smooth muscle cells (SMCs) and endothelial cells (ECs). It is synthesized at the inner face of the cell membrane by hyaluronan synthases 1 to 3 (HAS 1 to 3), followed by translocation to the outer surface and the intercellular space. 1 Recent in vitro investigations have shown that high (HMW) as well as low molecular (LMW) forms of HA influence important cellular functions, such as proliferation, migration, and secretory capabilities. [1][2][3][4] There seems to exist a delicately regulated balance between production, sizing, and removal of HA that is central to its biological functions during normal conditions. If this balance is disturbed, it has been hypothesized that disease may develop. 5 The notion that HA is likely to take part in the development of vascular pathologies has been nourished by a number of observations, which show altered HA amounts in several arterial disease entities such as diabetic angiopathy, atherosclerosis, and restenosis. 6 -8 During the build-up of the atherosclerotic plaques in humans, some areas with local accumulation of HA appear. 9 -11 This is in contrast to the situation in patients with diabetes in whom the HA accumulation is disseminated in tunica media and is regarded as one important element in a series of diffuse matrix changes in the vessels. 6,12 The diabetic angiopathy deserves some specific comments. First, a very high and equal frequency of cardiovascular disease (CVD) exists among men and...

Regulation and characteristics of vascular smooth muscle cell phenotypic diversity

“…51 Hyaluronan, a glycosaminoglycan which is present in the medial ECM, has also been shown to enhance proliferation and migration of SMCs. 52 Moreover, overexpression of hyaluronan by mouse SMCs accelerates the progression of atherosclerosis, 53 which is associated with SMC phenotypic modulation towards the synthetic phenotype.…”

The early- and late stages in phenotypic modulation of vascular smooth muscle cells: Differential roles for lysophosphatidic acid

“…Soluble biochemical factors, including platelet-derived growth factor (PDGF) [22][23][24][25], transforming growth factor (TGF)-β [26,27], and retinoic acid [28][29][30][31] have been shown to affect PM. Extracellular matrix molecules, such as heparin, fibrillar collagen type I, collagen type IV, and laminin have also been shown to have significant effects on PM [32][33][34][35][36][37][38][39].…”

Role of UDP-N-Acetylglucosamine (GlcNAc) and O-GlcNAcylation of Hyaluronan Synthase 2 in the Control of Chondroitin Sulfate and Hyaluronan Synthesis

“…The glycosaminoglycan hyaluronan (HA), other proteoglycans, including versican, and matrix metalloproteinases accumulate within the neointima and strongly induce SMC growth, motility, LDL binding, and monocyte recruitment, which promotes vessel thickening (2)(3)(4)(5). The crucial role of HA has been demonstrated in transgenic animals overexpressing HAS2 as well as in mice lacking the HA receptor CD44, which are prone to and protected from atherosclerosis, respectively (6,7).…”