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KMID : 0578320120330060563
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Molecules and Cells
2012 Volume.33 No. 6 p.563 ~ p.574
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Hyaluronic Acid Promotes Angiogenesis by Inducing RHAMM-TGFβ Receptor Interaction via CD44-PKCδ
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Park Deok-Bum
Kim Young-Mi
Kim Hyun-Ah
Kim Kyung-Jong
Lee Yun-Sil
Choe Jong-Seon
Hahn Jang-Hee
Lee Han-Soo
Jeon Jong-Wook
Choi Chul-Hee
Kim Young-Myeong
Jeoung Doo-Il
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Abstract
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Hyaluronic acid (HA) has been shown to promote angio-genesis. However, the mechanism behind this effect re-mains largely unknown. Therefore, in this study, the me-chanism of HA-induced angiogenesis was examined. CD44 and PKC delta 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 TGF beta receptor signaling. The induction of PAI-1 was dependent on CD44 and PKC delta. HA also induced an interaction between RHAMM and TGF beta receptor I, and induction of PAI-1 was dependent on RHAMM and TGF beta receptor I. Histone deacetylase 3 (HDAC3), which is de-creased 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 TGF beta 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 expres-sion of MMP-2. In this study, we provide a novel mecha-nism of HA-promoted angiogenesis, which involved RHAMM-TGF beta RI signaling necessary for induction of PAI-1.
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KEYWORD
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CD44, hyaluronic acid, PAI-1, RHAMM, TGF? signaling
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