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Originally published online as doi:10.2353/ajpath.2009.080515 on October 1, 2009

Published online before print October 1, 2009
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(American Journal of Pathology. 2009;175:1984-1992.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080515

Contribution of Macrophages to Angiogenesis Induced by Vascular Endothelial Growth Factor Receptor-3-Specific Ligands

Eui-Sang Chung*{dagger}, Sunil Kumar Chauhan*, Yiping Jin*, Shintaro Nakao{ddagger}, Ali Hafezi-Moghadam{ddagger}, Nico van Rooijen§, Qiang Zhang*, Lu Chen* and Reza Dana*{ddagger}

From the Schepens Eye Research Institute,* Harvard Medical School, Boston, Massachusetts; the Department of Ophthalmology,{dagger} Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea; the Department of Ophthalmology,{ddagger} Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts; and the Department of Molecular Cell Biology,§ Vrije Universiteit Medical Center, Amsterdam, The Netherlands

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.






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Copyright © 2009 by the American Society for Investigative Pathology.