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

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124 Scopus citations


Hyaluronic acid (HA) has been shown to promote angio-genesis. 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-pro-moted 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.

Original languageEnglish
Pages (from-to)563-574
Number of pages12
JournalMolecules and Cells
Issue number6
StatePublished - Jun 2012

Bibliographical note

Funding Information:
This work was supported by the Korea Research Foundation (C1001478-01-01, C1006272-01-01, C1007565-01-01 and C1006625-01-02) ; Korea Research Foundation Grant funded by the Korean Government [Ministry of Education, Science and Technology (MEST)]” (The Regional Research Universities Program/Medical & Bio-Materials Research Center); and the Regional Innovation Center Program (MEST).


  • CD44
  • Hyaluronic acid
  • PAI-1
  • TGFβ signaling


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