title: 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.
abstract: Angiogenesis or the formation of new blood vessels is important in the growth and metastatic potential of various cancers. Therefore, understanding the mechanism(s) by which angiogenesis occurs can have important therapeutic implications in numerous malignancies. We and others have demonstrated that low molecular weight hyaluronan (LMW-HA, ∼2500 Da) promotes endothelial cell (EC) barrier disruption and angiogenesis. However, the mechanism(s) by which this occurs is poorly defined. Our data indicate that treatment of human EC with LMW-HA induced CD44v10 association with the receptor-tyrosine kinase, EphA2, transactivation (tyrosine phosphorylation) of EphA2, and recruitment of the PDZ domain scaffolding protein, PATJ, to the cell periphery. Silencing (siRNA) CD44, EphA2, PATJ, or Dbs (RhoGEF) expression blocked LMW-HA-mediated angiogenesis (EC proliferation, migration, and tubule formation). In addition, silencing EphA2, PATJ, Src, or Dbs expression blocked LMW-HA-mediated RhoA activation. To translate our in vitro findings, we utilized a novel anginex/liposomal targeting of murine angiogenic endothelium with either CD44 or EphA2 siRNA and observed inhibition of LMW-HA-induced angiogenesis in implanted Matrigel plugs. Taken together, these results indicate LMW-HA-mediated transactivation of EphA2 is required for PATJ and Dbs membrane recruitment and subsequent RhoA activation required for angiogenesis. These results suggest that targeting downstream effectors of LMW-HA could be a useful therapeutic intervention for angiogenesis-associated diseases including tumor progression.
authors.affiliation: From the Department of Medicine, Section of Pulmonary and Critical Care and.
authors.forename: Frances E
authors.initials: FE
authors.lastname: Lennon
authors.affiliation: From the Department of Medicine, Section of Pulmonary and Critical Care and.
authors.forename: Tamara
authors.initials: T
authors.lastname: Mirzapoiazova
authors.affiliation: From the Department of Medicine, Section of Pulmonary and Critical Care and.
authors.forename: Nurbek
authors.initials: N
authors.lastname: Mambetsariev
authors.affiliation: From the Department of Medicine, Section of Pulmonary and Critical Care and.
authors.forename: Bolot
authors.initials: B
authors.lastname: Mambetsariev
authors.affiliation: Section of Hematology and Oncology University of Chicago, Chicago Illinois 60637.
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
authors.affiliation: From the Department of Medicine, Section of Pulmonary and Critical Care and psinglet@mail.bsd.uchicago.edu.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Singleton
mesh_terms: D000818:Animals; D018450:Disease Progression; D036383:Ephrin-A2 / Q000235:genetics* / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D009369:Neoplasms / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000502:physiology; D015533:Transcriptional Activation
chemical_list: D036383:Ephrin-A2; D006820:Hyaluronic Acid; D020794:Receptor Protein-Tyrosine Kinases
keywords: Anginex; Angiogenesis; CD44; Dbs; Endothelial Cell; EphA2; Hyaluronan; Hyaluronate; PATJ; Ras Homolog Gene Family, Member A (RhoA)