Murakami Masato, Zheng Yujuan, Hirashima Masanori, Suda Toshio, Morita Yohei, Ooehara Jun, Ema Hideo, Fong Guo-Hua, Shibuya Masabumi
Division of Genetics, Institute of Medical Science, University of Tokyo, Japan.
Arterioscler Thromb Vasc Biol. 2008 Apr;28(4):658-64. doi: 10.1161/ATVBAHA.107.150433. Epub 2008 Jan 3.
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.
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.
VEGFR1 signaling promotes lymphangiogenesis as well as angiogenesis mainly by increasing bone marrow-derived macrophage recruitment.
血管生成和淋巴管生成是复杂的现象，涉及多种生长因子和受体的相互作用。最近，我们已经证明，在角蛋白-14（K14）启动子驱动的Vegf-A转基因（Tg）小鼠中，不仅血管生成，而且淋巴管生成也受到刺激。然而，VEGFR1参与淋巴管生成的机制仍不清楚。
为了研究VEGFR1的酪氨酸激酶（TK）在K14 Vegf-A Tg小鼠淋巴管生成中的重要性，我们将K14 Vegf-A Tg小鼠与VEGFR1-TK缺陷小鼠杂交，以产生双突变K14 Vegf-A Tg Vegfr1 tk(-/-)小鼠。K14 Vegf-A Tg Vegfr1 tk(-/-)小鼠皮下组织中的淋巴管生成和血管生成均显著减少。为了探讨淋巴管生成减少的潜在机制，我们研究了单核细胞-巨噬细胞谱系细胞向皮肤的募集情况。在K14 Vegf-A Tg Vegfr1 tk(-/-)小鼠中，由VEGF-A驱动的表达VEGFR1的巨噬细胞的募集减少。与K14 Vegf-A Tg小鼠相比，接受VEGFR1-TK缺陷骨髓的Vegf-A Tg小鼠的巨噬细胞募集、淋巴管生成和血管生成均减少。
VEGFR1信号传导主要通过增加骨髓来源的巨噬细胞募集来促进淋巴管生成和血管生成。
