VEGFR1 tyrosine kinase signaling promotes lymphangiogenesis as well as angiogenesis indirectly via macrophage recruitment

Masato Murakami, Yujuan Zheng, Masanori Hirashima, Toshio Suda, Yohei Morita, Jun Ooehara, Hideo Ema, Guo Hua Fong, Masabumi Shibuya

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OBJECTIVE - Angiogenesis and lymphangiogenesis are complex phenomena that involve the interplay of several growth factors and receptors. Recently, we have demonstrated that in Keratin-14 (K14) promoter-driven Vegf-A transgenic (Tg) mice, not only angiogenesis but also lymphangiogenesis is stimulated. However, the mechanism by which VEGFR1 is involved in lymphangiogenesis remains unclear. METHODS AND RESULTS - To examine how important the tyrosine kinase (TK) of VEGFR1 is in lymphangiogenesis in K14 Vegf-A Tg mice, we crossed the K14 Vegf-A Tg mice with VEGFR1-TK-deficient mice to generate double mutant K14 Vegf-A Tg Vegfr1 tk mice. K14 Vegf-A Tg Vegfr1 tk mice exhibit a remarkable decrease in lymphangiogensis as well as angiogenesis in subcutaneous tissues. To address the mechanism underlying the decrease in lymphangiogensis, we investigated the recruitment of monocyte-macrophage-lineage cells into the skin. The recruitment of VEGFR1-expressing macrophages driven by VEGF-A was reduced in K14 Vegf-A Tg Vegfr1 tk mice. Vegf-A Tg mice that received VEGFR1-TK-deficient bone marrow showed a reduction of macrophage recruitment, lymphangiogenesis and angiogenesis compared with those in K14 Vegf-A Tg mice. CONCLUSIONS - VEGFR1 signaling promotes lymphangiogenesis as well as angiogenesis mainly by increasing bone marrow-derived macrophage recruitment.

Original languageEnglish
Pages (from-to)658-664
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number4
Publication statusPublished - 2008 Apr 1



  • Lymphangiogenesis
  • VEGF-A
  • VEGFR1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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