Blood vessel endothelial VEGFR-2 delays lymphangiogenesis: an endogenous trapping mechanism links lymph- and angiogenesis.
Angio- and lymphangiogenesis are inherently related processes. However, how blood and lymphatic vessels regulate each other is unknown. This work introduces a novel mechanism explaining the temporal and spatial relation of blood and lymphatic vessels. Vascular endothelial growth factor-A (VEGF-A) surprisingly reduced VEGF-C in the supernatant of blood vessel endothelial cells, suggesting growth factor (GF) clearance by the growing endothelium. The orientation of lymphatic sprouting toward angiogenic vessels and away from exogenous GFs was VEGF-C dependent. In vivo molecular imaging revealed higher VEGF receptor (R)-2 in angiogenic tips compared with normal vessels. Consistently, lymphatic growth was impeded in the angiogenic front. VEGF-C/R-2 complex in the cytoplasm of VEGF-A-treated endothelium indicated that receptor-mediated internalization causes GF clearance from the extracellular matrix. GF clearance by receptor-mediated internalization is a new paradigm explaining various characteristics of lymphatics.
Nakao
Shintaro
S
Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Zandi
Souska
S
Hata
Yasuaki
Y
Kawahara
Shuhei
S
Arita
Ryoichi
R
Schering
Alexander
A
Sun
Dawei
D
Melhorn
Mark I
MI
Ito
Yasuhiro
Y
Lara-Castillo
Nuria
N
Ishibashi
Tatsuro
T
Hafezi-Moghadam
Ali
A
D000818:Animals; D001808:Blood Vessels / Q000378:metabolism*; D002460:Cell Line; D003315:Cornea / Q000098:blood supply; D003593:Cytoplasm / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects; D042601:Lymphatic Vessels / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D042582:Vascular Endothelial Growth Factor C / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3