title: Overexpression of hyaluronan in the tunica media promotes the development of atherosclerosis.
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 alpha smooth-muscle-cell-actin (alphaSMA) 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.
authors.affiliation: The Research Laboratory for Biochemical Pathology, Aarhus University Hospital, Aarhus, Denmark. lwb@ki.au.dk.
authors.forename: Song
authors.initials: S
authors.lastname: Chai
authors.forename: Qing
authors.initials: Q
authors.lastname: Chai
authors.forename: Carl C
authors.initials: CC
authors.lastname: Danielsen
authors.forename: Peter
authors.initials: P
authors.lastname: Hjorth
authors.forename: Jene R
authors.initials: JR
authors.lastname: Nyengaard
authors.forename: Thomas
authors.initials: T
authors.lastname: Ledet
authors.forename: Yu
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Lars M
authors.initials: LM
authors.lastname: Rasmussen
authors.forename: Lise
authors.initials: L
authors.lastname: Wogensen
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D001696:Biomechanical Phenomena; D003925:Diabetic Angiopathies / Q000378:metabolism; D018450:Disease Progression; D004547:Elastic Tissue / Q000473:pathology; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis* / Q000737:chemistry; D006909:Hydroxyproline / Q000032:analysis; D006938:Hyperlipoproteinemia Type II / Q000150:complications / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000098:blood supply; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008970:Molecular Weight; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017540:Tunica Media / Q000378:metabolism* / Q000473:pathology; D001743:Urinary Bladder / Q000378:metabolism
chemical_list: D000199:Actins; D001057:Apolipoproteins E; D011993:Recombinant Fusion Proteins; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases; D006909:Hydroxyproline