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.

Antizyme Inhibitor 2 (AZIN2/ODCp) Stimulates Polyamine Uptake in Mammalian Cells

“…Moreover, AZIN1 is up-regulated in several human cancers (44) and is rapidly stimulated in cultured fibroblasts by serum and phorbol esters (45). AZIN1 is also up-regulated in capillary endothelial cells by fibroblast growth factor 2, a known angiogenic factor (46). Coincidentally, the human AZIN1 gene is located in a region of chromosome 8 that is amplified in some tumors (47,48).…”

Hyaluronan differently modulates TLR‐4 and the inflammatory response in mouse chondrocytes

“…Very small HA oligosaccharides also have unique specific biological activities. Oligomers of six disaccharides promote differentiation of the endothelial cells induced in response to the angiogenic effect of larger HA fragments [21]. Tetra and hexasaccharides are predominant products of hyaluronidase-mediated degradation.…”

Harnessing developmental processes for vascular engineering and regeneration

“…HA, a high-molecular-weight polysaccharide, is well-known as an important ECM component; it regulates vascular development by stimulating EC proliferation and cytokine/GF secretion (Takahashi et al, 2005;Mo et al, 2011). HA can be used in hydrogel scaffolds in conjunction with RGD and MMP-sensitive peptides to support vascular morphogenesis and network formation Yee et al, 2011;Kusuma et al, 2013).…”