Hyaluronan oligosaccharides are potential stimulators to angiogenesis via RHAMM mediated signal pathway in wound healing

Abstract

Clin Invest Med 2008; 31 (3): E106-E116. AbstractPurpose: To determine if oligosaccharides of hyaluronan (o-HA) promotes wound recovery by accelerating angiogenesis and to study the mechanisms by which o-HA stimulates endothelial cell (EC) proliferation. Methods: Using hyaluronidase digestion, we prepared a mixture of hyaluronan (HA) fragments sizesd 2 to 10 disaccharides units, and studied their effects on EC growth and migration in mimicking wound recovery in vitro. The effects of o-HA on EC growth in vitro were studied by counting cell numbers. The roles of 2 hyaluronan receptors on EC cells, CD44 and RHAMM (Receptor for HAMediated Motility), were studied in initiating signaling cascades, using immunoblot assay. Signal transduction was determined by blocking antibodies to CD44 and RHAMM. An in vitro wound healing model was prepared by scratching the cellular layer of cultured EC, and movement of cells into the denuded area was quantified. Results: o-HA was a strong stimulator to EC proliferation at low concentration 10 g/ml compared with native high molecular weight HA (n-HA) (P<0.01). Signal transduction may be initiated by o-HA via RHAMM receptor on EC membrane, but not CD44. In the in vitro model, the lesion area was nearly completely recovered when the EC layer was exposed to o-HA 40hrs post-injury, whereas the wound area remained half recovered pretreated with native undegraded large HA and control medium.(P <0.05 from 24 to 40hrs). Conclusion:Hyaluronan oligosaccharides may play a role in wound healing by increasing angiogenesis. o-HA-RHAMM binding dependent signal transduction pathway may be important in the regulation of angiogenesis associated with EC proliferation.

Transactivation of the Receptor-tyrosine Kinase Ephrin Receptor A2 Is Required for the Low Molecular Weight Hyaluronan-mediated Angiogenesis That Is implicated in Tumor Progression

“…Specifically, CD44 regulated HA-mediated adhesion, proliferation, and tube formation, whereas RHAMM regulated migration and in vivo angiogenesis. Gao et al (75) showed that RHAMM is the major receptor involved in HA fragment-induced angiogenesis during wound healing. Furthermore, Matou-Nasri et al (60) demonstrated that both CD44 and RHAMM are involved in HA fragment-induced BAEC angiogenesis.…”

The influence of hyaluronic acid on vascular endothelial cell proliferation and the relationship with ezrin/merlin expression

“…Some studies suggested that nHA/oHA acted via modulating the activity of related downstream signal molecules to influence cell functions [7,21]. Most studies concerned the activation of cellular signal molecules and the function of kinases [10], suggesting the probable existence of a Figure 6 The effects of oHA and nHA on ezrin/merlin mRNA expression after silencing of ezrin/merlin After ezrin-or merlin-targeting siRNA was transfected into HUVECs, 10 mg/ml oHA or 200 mg/ml nHA was added.…”

Hyaluronic Acid Mediated Enrichment of CD44 Expressing Glioblastoma Stem Cells in U251MG Xenograft Mouse Model

“…The CD44 binding to HA also has various outcomes based on the size of HA binding to CD44 such as proangiogenic and pro-inflammatory while nHA promoted anti-angiogenic and anti-inflammatory effects [16][17][18]. To assess the HA mediated enrichment of CD44, we cultured A172 and U251MG glioblastoma cells in both adherent and non-adherent conditions at a concentration of 100 µg/ml of HA.…”