title: Notch restricts lymphatic vessel sprouting induced by vascular endothelial growth factor.
abstract: Notch signaling plays a central role in cell-fate determination, and its role in lateral inhibition in angiogenic sprouting is well established. However, the role of Notch signaling in lymphangiogenesis, the growth of lymphatic vessels, is poorly understood. Here we demonstrate Notch pathway activity in lymphatic endothelial cells (LECs), as well as induction of delta-like ligand 4 (Dll4) and Notch target genes on stimulation with VEGF or VEGF-C. Suppression of Notch signaling by a soluble form of Dll4 (Dll4-Fc) synergized with VEGF in inducing LEC sprouting in 3-dimensional (3D) fibrin gel assays. Expression of Dll4-Fc in adult mouse ears promoted lymphangiogenesis, which was augmented by coexpressing VEGF. Lymphangiogenesis triggered by Notch inhibition was suppressed by a monoclonal VEGFR-2 Ab as well as soluble VEGF and VEGF-C/VEGF-D ligand traps. LECs transduced with Dll4 preferentially adopted the tip cell position over nontransduced cells in 3D sprouting assays, suggesting an analogous role for Dll4/Notch in lymphatic and blood vessel sprouting. These results indicate that the Notch pathway controls lymphatic endothelial quiescence, and explain why LECs are poorly responsive to VEGF compared with VEGF-C. Understanding the role of the Notch pathway in lymphangiogenesis provides further insight for the therapeutic manipulation of the lymphatic vessels.
authors.affiliation: Molecular/Cancer Biology Laboratory, Research Programs Unit, Institute for Molecular Medicine Finland and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Tuomas
authors.initials: T
authors.lastname: Tammela
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Andrey
authors.initials: A
authors.lastname: Anisimov
authors.forename: Tanja
authors.initials: T
authors.lastname: Holopainen
authors.forename: Seppo
authors.initials: S
authors.lastname: Kaijalainen
authors.forename: Terhi
authors.initials: T
authors.lastname: Karpanen
authors.forename: Kaisa
authors.initials: K
authors.lastname: Lehti
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D042783:Endothelial Cells / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D042583:Lymphangiogenesis / Q000502:physiology*; D042601:Lymphatic Vessels / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D051880:Receptors, Notch / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C571158:Dll4-Fc protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C064045:delta protein