title: Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3.
abstract: Vascular sprouting is a key process-driving development of the vascular system. In this study, we show that neuropilin-2 (Nrp2), a transmembrane receptor for the lymphangiogenic vascular endothelial growth factor C (VEGF-C), plays an important role in lymphatic vessel sprouting. Blocking VEGF-C binding to Nrp2 using antibodies specifically inhibits sprouting of developing lymphatic endothelial tip cells in vivo. In vitro analyses show that Nrp2 modulates lymphatic endothelial tip cell extension and prevents tip cell stalling and retraction during vascular sprout formation. Genetic deletion of Nrp2 reproduces the sprouting defects seen after antibody treatment. To investigate whether this defect depends on Nrp2 interaction with VEGF receptor 2 (VEGFR2) and/or 3, we intercrossed heterozygous mice lacking one allele of these receptors. Double-heterozygous nrp2vegfr2 mice develop normally without detectable lymphatic sprouting defects. In contrast, double-heterozygote nrp2vegfr3 mice show a reduction of lymphatic vessel sprouting and decreased lymph vessel branching in adult organs. Thus, interaction between Nrp2 and VEGFR3 mediates proper lymphatic vessel sprouting in response to VEGF-C.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 833, 75005 Paris, France.
authors.forename: Yunling
authors.initials: Y
authors.lastname: Xu
authors.forename: Li
authors.initials: L
authors.lastname: Yuan
authors.forename: Judy
authors.initials: J
authors.lastname: Mak
authors.forename: Luc
authors.initials: L
authors.lastname: Pardanaud
authors.forename: Maresa
authors.initials: M
authors.lastname: Caunt
authors.forename: Ian
authors.initials: I
authors.lastname: Kasman
authors.forename: Bruno
authors.initials: B
authors.lastname: Larrivée
authors.forename: Raquel
authors.initials: R
authors.lastname: Del Toro
authors.forename: Steven
authors.initials: S
authors.lastname: Suchting
authors.forename: Alexander
authors.initials: A
authors.lastname: Medvinsky
authors.forename: Jillian
authors.initials: J
authors.lastname: Silva
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Jean-Léon
authors.initials: JL
authors.lastname: Thomas
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Koch
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Anne
authors.initials: A
authors.lastname: Eichmann
authors.forename: Anil
authors.initials: A
authors.lastname: Bagri
mesh_terms: D000818:Animals; D048430:Cell Shape; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D005260:Female; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000166:cytology* / Q000196:embryology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D039943:Neuropilin-2 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D039943:Neuropilin-2; D042582:Vascular Endothelial Growth Factor C; C467483:vascular endothelial growth factor C, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3