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

doi:10.1007/s10059-012-2294-1

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

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

130 Scopus citations

Abstract

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 language	English
Pages (from-to)	563-574
Number of pages	12
Journal	Molecules and Cells
Volume	33
Issue number	6
DOIs	https://doi.org/10.1007/s10059-012-2294-1
State	Published - 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).

Keywords

CD44
Hyaluronic acid
PAI-1
RHAMM
TGFβ signaling

Access to Document

10.1007/s10059-012-2294-1

Cite this

@article{eb1adcb304ab4ac096054270865ecb93,

title = "Hyaluronic acid promotes angiogenesis by inducing RHAMM-TGFβ receptor interaction via CD44-PKCδ",

abstract = "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.",

keywords = "CD44, Hyaluronic acid, PAI-1, RHAMM, TGFβ signaling",

author = "Deokbum Park and Youngmi Kim and Hyunah Kim and Kyungjong Kim and Lee, {Yun Sil} and Jongseon Choe and Hahn, {Jang Hee} and Hansoo Lee and Jongwook Jeon and Chulhee Choi and Kim, {Young Myeong} and Dooil Jeoung",

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).",

year = "2012",

month = jun,

doi = "10.1007/s10059-012-2294-1",

language = "English",

volume = "33",

pages = "563--574",

journal = "Molecules and Cells",

issn = "1016-8478",

publisher = "Korean Society for Molecular and Cellular Biology",

number = "6",

}

TY - JOUR

T1 - Hyaluronic acid promotes angiogenesis by inducing RHAMM-TGFβ receptor interaction via CD44-PKCδ

AU - Park, Deokbum

AU - Kim, Youngmi

AU - Kim, Hyunah

AU - Kim, Kyungjong

AU - Lee, Yun Sil

AU - Choe, Jongseon

AU - Hahn, Jang Hee

AU - Lee, Hansoo

AU - Jeon, Jongwook

AU - Choi, Chulhee

AU - Kim, Young Myeong

AU - Jeoung, Dooil

N1 - 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).

PY - 2012/6

Y1 - 2012/6

N2 - 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.

AB - 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.

KW - CD44

KW - Hyaluronic acid

KW - PAI-1

KW - RHAMM

KW - TGFβ signaling

UR - http://www.scopus.com/inward/record.url?scp=84863466133&partnerID=8YFLogxK

U2 - 10.1007/s10059-012-2294-1

DO - 10.1007/s10059-012-2294-1

M3 - Article

C2 - 22610405

AN - SCOPUS:84863466133

SN - 1016-8478

VL - 33

SP - 563

EP - 574

JO - Molecules and Cells

JF - Molecules and Cells

IS - 6

ER -

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

Abstract

Bibliographical note

Keywords

Access to Document

Fingerprint

Cite this