title: Estradiol inhibits hyaluronic acid synthase 1 expression in human vascular smooth muscle cells.
abstract: Epidemiological and clinical data suggest that estrogen retards the progression of atherosclerosis. This study aims to elucidate whether the phenotypic regulation of human vascular smooth muscle cells (VSMC) by estrogen may involve effects on the hyaluronan matrix. VSMC were synchronized by serum withdrawal and subsequently stimulated with 0.001, 0.01, 0.1 and 1 μM estradiol (E(2)) in the presence or absence of platelet-derived growth factor BB (PDGF-BB) for 24 h. E(2) reduced mRNA-expression of hyaluronic acid synthase (HAS) 1 in the presence and absence of PDGF-BB. In contrast, HAS2- and HAS3-mRNA-expression were not affected. This E(2)-mediated effect on HAS1 mRNA-expression was accompanied by reduced hyaluronan secretion and a shift of HA toward lower molecular weight as evidenced by molecular sieve chromatography. The downregulation of HAS1 was abrogated by the estrogen receptor (ER) α and β antagonist ICI182780 and could be mimicked by the ERα-agonist propyl-pyrazole triol (PPT). On the contrary, the ERβ-agonist diarylpropionitrile (DPN) had no effect on HAS1 mRNA-expression. To investigate whether the downregulation of HAS1 was causally involved in the phenotypic regulation of human VSMC by E(2), lentiviral overexpression of HAS1 was conducted. Overexpression of HAS1 abrogated the inhibition of sustained ERK1/2 phosphorylation and in turn inhibition of DNA-synthesis by E(2). For the first time this study provides strong evidence that HAS1-driven HA-synthesis is a target of E(2) in human VSMC and that E(2) mediates part of its anti-proliferative effects through an ERα-dependent inhibition of HA-synthesis.
authors: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
authors: Till
authors: T
authors: Freudenberger
authors: Katharina
authors: K
authors: Röck
authors: Guang
authors: G
authors: Dai
authors: Selma
authors: S
authors: Dorn
authors: Peter
authors: P
authors: Mayer
authors: Hans-Karl
authors: HK
authors: Heim
authors: Jens W
authors: JW
authors: Fischer
mesh_terms: D000077214:Becaplermin; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000096:biosynthesis*; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004967:Estrogens; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D000077214:Becaplermin; D004958:Estradiol; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C523794:HAS1 protein, human; D000076002:Hyaluronan Synthases