Phosphorylation of Akt and ERK1/2 is required for VEGF-A/VEGFR2-induced proliferation and migration of lymphatic endothelium.
Phosphorylation of Akt and ERK1/2 is required for VEGF-A/VEGFR2-induced proliferation and migration of lymphatic endothelium.
复制标题
DOI：
10.1371/journal.pone.0028947
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Brekken RA
中科院分区：
文献类型：
--
作者：
Dellinger MT;Brekken RA
越来越多的证据表明，血管内皮生长因子-A (VEGF-A)（受体酪氨酸激酶 VEGFR1 和 VEGFR2 的配体）可促进淋巴管生成。然而，VEGF-A 诱导淋巴管生长的潜在机制仍不清楚。在这里，我们报道 VEGFR2，而不是 VEGFR1，是调节 VEGF-A 诱导的淋巴管生成的主要受体。我们发现，用全人单克隆抗体 r84 特异性抑制 VEGF-A/VEGFR2 信号传导可显着抑制 MDA-MB-231 肿瘤中的淋巴管生成。原代人真皮淋巴内皮细胞 (LEC) 的体外实验表明，阻断 VEGF-A 对 VEGFR2（而非 VEGFR1）的激活可显着抑制 VEGF-A 诱导的 LEC 增殖和迁移。我们发现 VEGF-A 对 LEC 的刺激会导致 VEGFR2（Tyr 951、1054、1059、1175 和 1214）磷酸化，随后触发 ERK1/2 的 PKC 依赖性磷酸化和 Akt 的 PI3-K 依赖性磷酸化。此外，我们证明抑制 ERK1/2 和 Akt 磷酸化的抑制剂可显着阻断 VEGF-A 诱导的 LEC 增殖和迁移。总之，这些结果揭示了调节 VEGF-A 诱导的 LEC 增殖和迁移的机制，揭示了 VEGFR2 是淋巴管内皮上主要信号 VEGF-A 受体，并表明靶向 VEGF-A/VEGFR2 轴的治疗药物可用于阻断淋巴管的病理形成。
There is growing evidence that vascular endothelial growth factor-A (VEGF-A), a ligand of the receptor tyrosine kinases VEGFR1 and VEGFR2, promotes lymphangiogenesis. However, the underlying mechanisms by which VEGF-A induces the growth of lymphatic vessels remain poorly defined. Here we report that VEGFR2, not VEGFR1, is the primary receptor regulating VEGF-A-induced lymphangiogenesis. We show that specific inhibition of VEGF-A/VEGFR2 signaling with the fully human monoclonal antibody r84 significantly inhibits lymphangiogenesis in MDA-MB-231 tumors. In vitro experiments with primary human dermal lymphatic endothelial cells (LECs) demonstrate that blocking VEGF-A activation of VEGFR2, not VEGFR1, significantly inhibits VEGF-A-induced proliferation and migration of LECs. We show that VEGF-A stimulation of LECs leads to the phosphorylation of VEGFR2 (Tyr 951, 1054, 1059, 1175, and 1214) which subsequently triggers PKC dependent phosphorylation of ERK1/2 and PI3-K dependent phosphorylation of Akt. Additionally, we demonstrate that inhibitors that suppress the phosphorylation of ERK1/2 and Akt significantly block VEGF-A- induced proliferation and migration of LECs. Together, these results shed light on the mechanisms regulating VEGF-A-induced proliferation and migration of LECs, reveal that VEGFR2 is the primary signaling VEGF-A receptor on lymphatic endothelium, and suggest that therapeutic agents targeting the VEGF-A/VEGFR2 axis could be useful in blocking the pathological formation of lymphatic vessels.
登录
查看更多内容
影响因子：
6
作者：
Hirakawa, S;Hong, YK;Detmar, M
通讯作者：
Detmar, M
影响因子：
4.8
作者：
Hong, YK;Lange-Asschenfeldt, B;Detmar, M
通讯作者：
Detmar, M
影响因子：
5.7
作者：
Roland, Christina L.;Dineen, Sean P.;Brekken, Rolf A.
通讯作者：
Brekken, Rolf A.
影响因子：
4.8
作者：
Saaristo, A;Veikkola, T;Alitalo, K
通讯作者：
Alitalo, K
影响因子：
11.2
作者：
Lahdenranta J;Hagendoorn J;Padera TP;Hoshida T;Nelson G;Kashiwagi S;Jain RK;Fukumura D
通讯作者：
Fukumura D