Hyaluronectin blocks the stimulatory effect of hyaluronan-derived fragments on endothelial cells during angiogenesis in vitro.

Hyaluronic acid (HA) is a glycosaminoglycan of the extracellular matrix. Its fragmentation by the hyaluronidase, secreted by tumor cells, facilitates tumor invasion and the HA degradation products generated stimulate angiogenesis. We report here that the HA-binding protein hyaluronectin (HN) inhibits the stimulatory effect of HA-derived fragments on the proliferation and migration of endothelial cells in vitro, and hampers the organization of endothelial cells into capillary-like structures. Since HN strongly inhibits endothelial cell adhesion to immobilized HA, it is postulated that HN acts by impairing the binding to endothelial cells of HA fragments generated by hyaluronidase, thereby neutralizing the effect of HA degradation products on angiogenesis. Our results reveal a new mechanism by which the angiogenesis induced by HA fragments is modulated by HN.