Contribution of macrophages to angiogenesis induced by vascular endothelial growth factor receptor-3-specific ligands

Eui Sang Chung, Sunil Kumar Chauhan, Yiping Jin, Shintaro Nakao, Ali Hafezi-Moghadam, Nico Van Rooijen, Qiang Zhang, Lu Chen, Reza Dana

Research output: Contribution to journalArticlepeer-review

67 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1984-1992
Number of pages9
JournalAmerican Journal of Pathology
Volume175
Issue number5
DOIs
Publication statusPublished - 2009

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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