Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression.
Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression.
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DOI：
10.1172/jci155478
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发表时间：
2022-08-01
影响因子：
15.9
通讯作者：
Alitalo, Kari
中科院分区：
文献类型：
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作者：
Korhonen, Emilia A.;Murtomaki, Aino;Jha, Sawan Kumar;Anisimov, Andrey;Pink, Anne;Zhang, Yan;Stritt, Simon;Liaqat, Inam;Stanczuk, Lukas;Alderfer, Laura;Sun, Zhiliang;Kapiainen, Emmi;Singh, Abhishek;Sultan, Ibrahim;Lantta, Anni;Leppanen, Veli-Matti;Eklund, Lauri;He, Yulong;Augustin, Hellmut G.;Vaahtomeri, Kari;Saharinen, Pipsa;Makinen, Taija;Alitalo, Kari
血管内皮生长因子 C (VEGF-C) 通过 VEGF 受体 3 (VEGFR3) 诱导淋巴管生成，VEGF 受体 3 由人类原发性淋巴水肿中最常见的突变基因编码。血管生成素 (Angs) 及其 Tie 受体调节淋巴管发育，最近在人类原发性淋巴水肿中发现了 ANGPT2 基因的突变。然而，Ang2 活性在淋巴管生成中的机制基础尚不完全清楚。在这里，我们使用基因删除、阻断 Abs、转基因诱导和基因转移来研究 Ang2、其 Tie2 受体和 Tie1 如何调节淋巴管。我们发现 VEGF-C 诱导的淋巴内皮细胞 (LEC) 分泌 Ang2 参与磷酸肌醇 3 激酶 (PI3K) 下游 Akt 的完全激活。新生儿删除 LEC 中编码 Tie 受体或 Ang2 的基因，或施用 Ang2 阻断抗体可减少 LEC 上 VEGFR3 的呈递并抑制淋巴管生成。在删除 PI3K 催化 p110α 亚基或小分子抑制位于 Ang2 下游的组成型活性 PI3K 后，在 LEC 中观察到类似的效果。在成年小鼠中，删除 Tie 受体或阻断 Ang2 也会减少 VEGF-C 诱导的淋巴管生成。我们的结果揭示了 VEGF-C 和 Ang 信号通路之间的重要串扰，并提出了通过靶向 Ang2/Tie/PI3K 信号传导来治疗操纵淋巴管生成的新途径。
Vascular endothelial growth factor C (VEGF-C) induces lymphangiogenesis via VEGF receptor 3 (VEGFR3), which is encoded by the most frequently mutated gene in human primary lymphedema. Angiopoietins (Angs) and their Tie receptors regulate lymphatic vessel development, and mutations of the ANGPT2 gene were recently found in human primary lymphedema. However, the mechanistic basis of Ang2 activity in lymphangiogenesis is not fully understood. Here, we used gene deletion, blocking Abs, transgene induction, and gene transfer to study how Ang2, its Tie2 receptor, and Tie1 regulate lymphatic vessels. We discovered that VEGF-C–induced Ang2 secretion from lymphatic endothelial cells (LECs) was involved in full Akt activation downstream of phosphoinositide 3 kinase (PI3K). Neonatal deletion of genes encoding the Tie receptors or Ang2 in LECs, or administration of an Ang2-blocking Ab decreased VEGFR3 presentation on LECs and inhibited lymphangiogenesis. A similar effect was observed in LECs upon deletion of the PI3K catalytic p110α subunit or with small-molecule inhibition of a constitutively active PI3K located downstream of Ang2. Deletion of Tie receptors or blockade of Ang2 decreased VEGF-C–induced lymphangiogenesis also in adult mice. Our results reveal an important crosstalk between the VEGF-C and Ang signaling pathways and suggest new avenues for therapeutic manipulation of lymphangiogenesis by targeting Ang2/Tie/PI3K signaling.