Molecules and Cells

, Volume 33, Issue 6, pp 563–574 | Cite as

Hyaluronic acid promotes angiogenesis by inducing RHAMM-TGFβ receptor interaction via CD44-PKCδ

  • Deokbum Park
  • Youngmi Kim
  • Hyunah Kim
  • Kyungjong Kim
  • Yun-Sil Lee
  • Jongseon Choe
  • Jang-Hee Hahn
  • Hansoo Lee
  • Jongwook Jeon
  • Chulhee Choi
  • Young-Myeong Kim
  • Dooil Jeoung
Research Article

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.

Keywords

CD44 hyaluronic acid PAI-1 RHAMM TGFβ signaling 

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Copyright information

© The Korean Society for Molecular and Cellular Biology and Springer Netherlands 2012

Authors and Affiliations

  • Deokbum Park
    • 1
  • Youngmi Kim
    • 1
  • Hyunah Kim
    • 1
  • Kyungjong Kim
    • 1
  • Yun-Sil Lee
    • 2
  • Jongseon Choe
    • 3
  • Jang-Hee Hahn
    • 3
  • Hansoo Lee
    • 1
  • Jongwook Jeon
    • 4
  • Chulhee Choi
    • 4
  • Young-Myeong Kim
    • 3
  • Dooil Jeoung
    • 1
  1. 1.School of Biological Sciences, College of Natural SciencesKangwon National UniversityChuncheonKorea
  2. 2.College of PharmacyEwha Womans UniversitySeoulKorea
  3. 3.School of MedicineKangwon National UniversityChunchonKorea
  4. 4.Cell Signaling and BioImaging Laboratory, Department of Bio and Brain EngineeringKorea Advanced Institute of Science and TechnologyDaejeonKorea

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