title: Low molecular weight hyaluronan induces lymphangiogenesis through LYVE-1-mediated signaling pathways.
abstract: Hyaluronan (HA), a large nonsulfated glycosaminogycan in the extracellular matrix, whose degraded fragments termed as low molecular weight hyaluronan (LMW-HA), has been reported as an important regulator of angiogenesis. However, little is known about the influence of LMW-HA on lymphangiogenesis. In this study, we try to explore the in vitro effects of LMW-HA on lymphangiogenesis and identify the underlying molecular mechanisms. Our results showed that LMW-HA stimulation significantly increased lymphatic endothelial cells (LECs) proliferation, migration and tube formation. Further experiments demonstrated that LMW-HA altered actin cytoskeleton rearrangement and increased the formation of intense stress fibers, lamellipodia and filopodia. Mechanistically, LMW-HA stimulation resulted in rapid tyrosine phosphorylation of protein kinase C α/βII (PKCα/βII) and extracellular-regulated kinase 1/2 (ERK1/2). Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), a homologue of CD44, is the main cell surface receptor for HA in LECs. Blocking the binding interaction of LMW-HA with LYVE-1 using neutralizing anti-LYVE-1 antibodies significantly inhibited LECs proliferation, migration, tube formation and signal transduction induced by LMW-HA, suggesting that LMW-HA may play a critical role in the processes required for lymphangiogenesis through interactions with its receptor LYVE-1 and triggering intracellular signal cascades.
authors.affiliation: Department of Molecular Biology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, PR China.
authors.forename: Man
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Molecular Biology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Molecular Biology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, PR China.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Molecular Biology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, PR China.
authors.forename: Yiqing
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Molecular Biology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, PR China.
authors.forename: Cuixia
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Molecular Biology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, PR China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology and Clinical Laboratory, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000494:pharmacology*; D042583:Lymphangiogenesis / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D026901:Membrane Transport Proteins; D051379:Mice; D008970:Molecular Weight; D011494:Protein Kinases / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D006023:Glycoproteins; D006820:Hyaluronic Acid; D026901:Membrane Transport Proteins; D011494:Protein Kinases; C492273:LYVE1 protein, mouse