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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:658.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

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

From the Division of Genetics (M.M., Y.Z., M.S.), Institute of Medical Science, University of Tokyo, Japan; the Department of Cell Differentiation (M.H., T.S.), The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, Japan; the Division of Stem Cell Therapy (Y.M., J.O., H.E.), Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Japan; the Center for Vascular Biology (G.-H.F.), Department of Cell Biology, University of Connecticut Health Center, Farmington; and the Department of Molecular Oncology (M.S.), Tokyo Medical and Dental University, Tokyo, Japan.

Correspondence to Dr Masabumi Shibuya, Department of Molecular Oncology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. E-mail shibuya{at}ims.u-tokyo.ac.jp

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.

Vegf-A transgenic (Tg) mice show not only angiogenesis but also lymphangiogenesis. To examine how important the tyrosine kinase (TK) of VEGFR1 in lymphangiogenesis, we crossed them with VEGFR1-TK–deficient mice. Double mutant mice demonstrated a remarkable decrease in lymphangiogenesis. We found that VEGFR1-signaling promotes lymphangiogenesis indirectly via macrophage recruitment.

Key Words: VEGF-A • VEGFR1 • lymphangiogenesis

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VEGFR1 for Lymphangiogenesis: An Alternative Signaling Pathway?

Yasufumi Sato
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