Contribution of macrophages to angiogenesis induced by vascular endothelial growth factor receptor-3-specific ligands.
Vascular endothelial growth factor receptor (VEGFR)-2 is a major stimulator of hemangiogenesis (HA), whereas VEGFR-3 stimulates lymphangiogenesis (LA). Contrary to this understanding, we demonstrate that implantation of pellets containing VEGFR-3-specific ligands (VEGF-C156S and recombinant murine VEGF-D) into the corneal stroma induce not only LA but also robust HA characterized by blood vessels that are positive for VEGFR-3 expression. The implantation of pellets containing VEGFR-3-specific ligands also leads to the recruitment of VEGF-A-secreting macrophages. Depletion of these infiltrating macrophages using clodronate-liposome administration shows a significant reduction in HA as well as LA. Blockade of either VEGFR-2 or VEGFR-3 signaling reduces both HA and LA; however, the percent reduction of HA is greater in the VEGFR-2 blockade group. In addition, in the VEGFR-3 blockade group, the percent reduction of HA is significantly greater with VEGFR-3-specific ligands than that by VEGF-A or VEGF-C. Collectively, our data suggest that VEGFR-3-specific signaling can induce new blood vessels, to which macrophages contribute a major role, and signify its potential as an additional therapeutic target to the existing VEGF-A/VEGFR-2 signaling-based antiangiogenesis strategies.
Chung
Eui-Sang
ES
Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA.
Chauhan
Sunil Kumar
SK
Jin
Yiping
Y
Nakao
Shintaro
S
Hafezi-Moghadam
Ali
A
van Rooijen
Nico
N
Zhang
Qiang
Q
Chen
Lu
L
Dana
Reza
R
D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D004002:Clodronic Acid / Q000494:pharmacology; D003315:Cornea / Q000098:blood supply / Q000166:cytology; D006023:Glycoproteins / Q000378:metabolism; D007113:Immunity, Innate; D008024:Ligands; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D042583:Lymphangiogenesis / Q000502:physiology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; D050071:Bone Density Conservation Agents; D004002:Clodronic Acid; D006023:Glycoproteins; D008024:Ligands; D008081:Liposomes; D026901:Membrane Transport Proteins; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; C492273:LYVE1 protein, mouse