title: VEGFR1 tyrosine kinase signaling promotes lymphangiogenesis as well as angiogenesis indirectly via macrophage recruitment.
abstract: 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.
  
  
  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.
authors.affiliation: Division of Genetics, Institute of Medical Science, University of Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Murakami
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Zheng
authors.forename: Masanori
authors.initials: M
authors.lastname: Hirashima
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.forename: Yohei
authors.initials: Y
authors.lastname: Morita
authors.forename: Jun
authors.initials: J
authors.lastname: Ooehara
authors.forename: Hideo
authors.initials: H
authors.lastname: Ema
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Fong
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002199:Capillary Permeability / Q000502:physiology; D005260:Female; D042583:Lymphangiogenesis / Q000502:physiology*; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; C467480:vascular endothelial growth factor A, mouse; C467483:vascular endothelial growth factor C, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1