Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Angiogenesis Inhibitors / genetics
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Angiogenesis Inhibitors / metabolism
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Animals
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Bone Density Conservation Agents / pharmacology
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Clodronic Acid / pharmacology
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Cornea / blood supply
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Cornea / cytology
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Glycoproteins / metabolism
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Immunity, Innate
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Ligands
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Liposomes / chemistry
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Liposomes / metabolism
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Lymphangiogenesis / physiology
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / metabolism*
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Male
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Membrane Transport Proteins
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Mice
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Mice, Inbred BALB C
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Neovascularization, Physiologic*
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Signal Transduction / physiology
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
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Vascular Endothelial Growth Factor C / genetics
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Vascular Endothelial Growth Factor C / metabolism
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Vascular Endothelial Growth Factor D / genetics
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Vascular Endothelial Growth Factor D / metabolism
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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Vascular Endothelial Growth Factor Receptor-3 / genetics
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Vascular Endothelial Growth Factor Receptor-3 / metabolism*
Substances
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Angiogenesis Inhibitors
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Bone Density Conservation Agents
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Glycoproteins
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Ligands
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Liposomes
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Membrane Transport Proteins
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factor C
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Vascular Endothelial Growth Factor D
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Xlkd1 protein, mouse
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Clodronic Acid
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Vascular Endothelial Growth Factor Receptor-2
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Vascular Endothelial Growth Factor Receptor-3