VEGFR1 tyrosine kinase signaling promotes lymphangiogenesis as well as angiogenesis indirectly via macrophage recruitment
VEGFR1 tyrosine kinase signaling promotes lymphangiogenesis as well as angiogenesis indirectly via macrophage recruitment
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DOI：
10.1161/atvbaha.107.150433
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发表时间：
2008-04-01
影响因子：
8.7
通讯作者：
Shibuya, Masabumi
中科院分区：
文献类型：
--
作者：
Murakami, Masato;Zheng, Yujuan;Shibuya, Masabumi
目的-血管生成和淋巴管生成是一个复杂的现象，涉及到几个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，不仅血管生成，而且淋巴管生成刺激。方法和结果-为了研究VEGFR 1的酪氨酸激酶（TK）在K14 Vegf-A Tg小鼠的淋巴管生成中的重要性，我们将K14 Vegf-A Tg小鼠与Vegfr 1-tk缺陷小鼠杂交以产生双突变K14 Vegf-A Tg Vegfr 1 tk（-/-）小鼠。K14 Vegf-A Tg Vegfr 1 tk（-/-）小鼠皮下组织中的淋巴管生成和血管生成显着减少。为了解决淋巴管生成减少的机制，我们研究了单核细胞-巨噬细胞系细胞向皮肤中的募集。在K14 Vegf-A Tg Vegfr 1 tk（-/-）小鼠中，VEGF-A驱动的表达VEGFR 1的巨噬细胞的募集减少。与K14 Vegf-A Tg小鼠相比，接受Vegfr 1-tk缺陷骨髓的Vegf-A Tg小鼠显示巨噬细胞募集、淋巴管生成和血管生成减少。结论-VEGFR 1信号传导主要通过增加骨髓源性巨噬细胞募集来促进淋巴管生成和血管生成。
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.