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J. Biol. Chem., Vol. 280, Issue 25, 24195-24204, June 24, 2005

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Hyaluronan Fragments Induce Endothelial Cell Differentiation in a CD44- and CXCL1/GRO1-dependent Manner^*boxs

Yoshinori Takahashi, Lingli Li, Masaru Kamiryo, Trias Asteriou, Aristidis Moustakas, Hidetoshi Yamashita¶, and Paraskevi Heldin||**

From the Ludwig Institute for Cancer Research, Box 595, Biomedical Center, Uppsala University, S-751 24 Uppsala, Sweden, the ^||Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Biomedical Center, S-751 23 Uppsala, Sweden, and the ^¶Department of Ophthalmology, Yamagata University, School of Medicine, 2-2-2 lidanishi, Yamagata, Japan 990-9585

Hyaluronan is a glycosaminoglycan of the extracellular matrix. In tumors and during chronic inflammatory diseases, hyaluronan is degraded to smaller fragments, which are known to stimulate endothelial cell differentiation. In this study, we have compared the molecular mechanisms through which hyaluronan dodecasaccharides (HA12), and the known angiogenic factor, fibroblast growth factor 2 (FGF-2), induce capillary endothelial cell sprouting in a three-dimensional collagen gel. The gene expression profiles of unstimulated and HA12- or FGF-2-stimulated endothelial cells were compared using a microarray analysis approach. The data revealed that both FGF-2 and HA12 promoted endothelial cell morphogenesis in a process depending on the expression of ornithine decarboxylase (Odc) and ornithine decarboxylase antizyme inhibitor (Oazi) genes. Among the genes selectively up-regulated in response to HA12 was the chemokine CXCL1/GRO1 gene. The notion that the induction of CXCL1/GRO1 is of importance for HA12-induced endothelial cell sprouting was supported by the fact that morphogenesis was inhibited by antibodies specifically neutralizing the CXCL1/GRO1 protein product. HA12-stimulated endothelial cell differentiation was exerted via binding to CD44 since it was inhibited by antibodies blocking CD44 function. Our data show that hyaluronan fragments and FGF-2 affect endothelial cell morphogenesis by the induction of overlapping but also by distinct sets of genes.

Received for publication, October 20, 2004 , and in revised form, March 18, 2005.

^* This work was supported in part by grants from the Swedish Cancer Society (3446-B03-10XBC). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^boxs The on-line version of this article (available at http://www.jbc.org) contains six supplemental tables corresponding to Tables 2-4.

Present address: Dept. of Ophthalmology, Yamagata University, School of Medicine, 2-2-2 lidanishi, Yamagata, Japan 990-9585.

^** To whom correspondence should be addressed. Tel.: 00-46-18-4714261; Fax: 00-46-18-4714975; E-mail: Paraskevi.Heldin{at}imbim.uu.se.

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