Role of VEGF-D and VEGFR-3 in developmental lymphangiogenesis, a chemicogenetic study in Xenopus tadpoles.
The importance of the lymphangiogenic factor VEGF-D and its receptor VEGFR-3 in early lymphatic development remains largely unresolved. We therefore investigated their role in Xenopus laevis tadpoles, a small animal model allowing chemicogenetic dissection of developmental lymphangiogenesis. Single morpholino antisense oligo knockdown of xVEGF-D did not affect lymphatic commitment, but transiently impaired lymphatic endothelial cell (LEC) migration. Notably, combined knockdown of xVEGF-D with xVEGF-C at suboptimal morpholino concentrations resulted in more severe migration defects and lymphedema formation than the corresponding single knockdowns. Knockdown of VEGFR-3 or treatment with the VEGFR-3 inhibitor MAZ51 similarly impaired lymph vessel formation and function and caused pronounced edema. VEGFR-3 silencing by morpholino knockdown, MAZ51 treatment, or xVEGF-C/D double knockdown also resulted in dilation and dysfunction of the lymph heart. These findings document a critical role of VEGFR-3 in embryonic lymphatic development and function, and reveal a previously unrecognized modifier role of VEGF-D in the regulation of embryonic lymphangiogenesis in frog embryos.
Ny
Annelii
A
Vesalius Research Center, VIB-KU Leuven, Leuven, Belgium.
Koch
Marta
M
Vandevelde
Wouter
W
Schneider
Martin
M
Fischer
Christian
C
Diez-Juan
Antonio
A
Neven
Elke
E
Geudens
Ilse
I
Maity
Sunit
S
Moons
Lieve
L
Plaisance
Stéphane
S
Lambrechts
Diether
D
Carmeliet
Peter
P
Dewerchin
Mieke
M
D000818:Animals; D020868:Gene Silencing; D007814:Larva / Q000254:growth & development; D042583:Lymphangiogenesis / Q000235:genetics / Q000502:physiology*; D042601:Lymphatic Vessels / Q000002:abnormalities / Q000196:embryology; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D042643:Vascular Endothelial Growth Factor D / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D029867:Xenopus Proteins / Q000235:genetics / Q000502:physiology*; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000254:growth & development* / Q000502:physiology*
D020319:Oligodeoxyribonucleotides, Antisense; D042643:Vascular Endothelial Growth Factor D; D029867:Xenopus Proteins; D040321:Vascular Endothelial Growth Factor Receptor-3