title: Hyaluronic acid promotes angiogenesis by inducing RHAMM-TGFβ receptor interaction via CD44-PKCδ.
abstract: Hyaluronic acid (HA) has been shown to promote angiogenesis. However, the mechanism behind this effect remains largely unknown. Therefore, in this study, the mechanism of HA-induced angiogenesis was examined. CD44 and PKCδ were shown to be necessary for induction of the receptor for HA-mediated cell motility (RHAMM), a HA-binding protein. RHAMM was necessary for HA-promoted cellular invasion and endothelial cell tube formation. Cytokine arrays showed that HA induced the expression of plasminogen activator-inhibitor-1 (PAI), a downstream target of TGFβ receptor signaling. The induction of PAI-1 was dependent on CD44 and PKCδ. HA also induced an interaction between RHAMM and TGFβ receptor I, and induction of PAI-1 was dependent on RHAMM and TGFβ receptor I. Histone deacetylase 3 (HDAC3), which is decreased by HA via rac1, reduced induction of plasminogen activator inhibitor-1 (PAI-1) by HA. ERK, which interacts with RHAMM, was necessary for induction of PAI-1 by HA. Snail, a downstream target of TGFβ signaling, was also necessary for induction of PAI-1. The down regulation of PAI-1 prevented HA from enhancing endothelial cell tube formation and from inducing expression of angiogenic factors, such as ICAM-1, VCAM-1 and MMP-2. HDAC3 also exerted reduced expression of MMP-2. In this study, we provide a novel mechanism of HA-promoted angiogenesis, which involved RHAMM-TGFβRI signaling necessary for induction of PAI-1.
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Korea.
authors.forename: Deokbum
authors.initials: D
authors.lastname: Park
authors.forename: Youngmi
authors.initials: Y
authors.lastname: Kim
authors.forename: Hyunah
authors.initials: H
authors.lastname: Kim
authors.forename: Kyungjong
authors.initials: K
authors.lastname: Kim
authors.forename: Yun-Sil
authors.initials: YS
authors.lastname: Lee
authors.forename: Jongseon
authors.initials: J
authors.lastname: Choe
authors.forename: Jang-Hee
authors.initials: JH
authors.lastname: Hahn
authors.forename: Hansoo
authors.initials: H
authors.lastname: Lee
authors.forename: Jongwook
authors.initials: J
authors.lastname: Jeon
authors.forename: Chulhee
authors.initials: C
authors.lastname: Choi
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
authors.forename: Dooil
authors.initials: D
authors.lastname: Jeoung
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000494:pharmacology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009479:Neuropeptides / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051745:Protein Kinase C-delta / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein; D000099186:Histone Deacetylase 3
chemical_list: D043925:Angiogenesis Inducing Agents; D016326:Extracellular Matrix Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D006655:Histone Deacetylases; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D020778:Matrix Metalloproteinase 2; D009479:Neuropeptides; D017395:Plasminogen Activator Inhibitor 1; D051745:Protein Kinase C-delta; D018125:Receptors, Transforming Growth Factor beta; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000099186:Histone Deacetylase 3; C497483:CD44 protein, human; C484602:Rac1 protein, mouse; C098946:hyaluronan-mediated motility receptor; C467480:vascular endothelial growth factor A, mouse; C522362:Mmp2 protein, mouse