title: Hyaluronan fragments induce endothelial cell differentiation in a CD44- and CXCL1/GRO1-dependent manner.
abstract: 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.
authors.affiliation: Ludwig Institute for Cancer Research, Box 595, Biomedical Center, Uppsala University, S-751 24 Uppsala, Sweden.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Lingli
authors.initials: L
authors.lastname: Li
authors.forename: Masaru
authors.initials: M
authors.lastname: Kamiryo
authors.forename: Trias
authors.initials: T
authors.lastname: Asteriou
authors.forename: Aristidis
authors.initials: A
authors.lastname: Moustakas
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Yamashita
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Heldin
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology*; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000502:physiology*; D017931:DNA Primers; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D020869:Gene Expression Profiling; D018960:Hyaluronan Receptors / Q000502:physiology*; D006820:Hyaluronic Acid / Q000737:chemistry / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; D017931:DNA Primers; D018960:Hyaluronan Receptors; D036341:Intercellular Signaling Peptides and Proteins; D016222:Fibroblast Growth Factor 2; D006820:Hyaluronic Acid