Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3.
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.
Xu
Yunling
Y
Institut National de la Santé et de la Recherche Médicale, Unité 833, 75005 Paris, France.
Yuan
Li
L
Mak
Judy
J
Pardanaud
Luc
L
Caunt
Maresa
M
Kasman
Ian
I
Larrivée
Bruno
B
Del Toro
Raquel
R
Suchting
Steven
S
Medvinsky
Alexander
A
Silva
Jillian
J
Yang
Jian
J
Thomas
Jean-Léon
JL
Koch
Alexander W
AW
Alitalo
Kari
K
Eichmann
Anne
A
Bagri
Anil
A
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*
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