c-Jun N-Terminal Kinase Mediated VEGFR2 Sustained Phosphorylation is Critical for VEGFA-Induced Angiogenesis In Vitro and In Vivo
c-Jun N-Terminal Kinase Mediated VEGFR2 Sustained Phosphorylation is Critical for VEGFA-Induced Angiogenesis In Vitro and In Vivo
复制标题
c-Jun N 端激酶介导的 VEGFR2 持续磷酸化对于 VEGFA 诱导的体外和体内血管生成至关重要
DOI：
10.1007/s12013-012-9363-0
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发表时间：
2012-05
影响因子：
2.6
通讯作者：
Zhengtao Wang
中科院分区：
文献类型：
--
作者：
Kaikai Shen;Lili Ji;Bin Lu;Zhengtao Wang
c-Jun N-末端激酶/应激激活蛋白激酶（JNK/SAPK）参与细胞周期、增殖、凋亡等多种细胞功能的调节。然而，JNK/SAPK是否直接调节血管内皮生长因子A（VEGFA）诱导的人脐静脉内皮细胞（HUVECs）的血管生成尚未完全阐明。本研究首次证明了VEGF诱导的血管生成反应，包括细胞活力的增加，迁移，并在HUVECs中以浓度依赖的方式管形成。VEGFA可诱导JNK/SAPK、p38激酶和细胞外信号调节激酶1和2（ERK 1/2）的激活，而JNK/SAPK抑制剂SP 600125和特异性siRNA均阻断VEGFA诱导的所有血管生成作用。此外，VEGFA诱导ASK 1、SEK 1/MKK 4、MKK 7和c-Jun的磷酸化，这些是JNK/SAPK的上游或下游信号。此外，体内基质胶栓塞试验进一步表明，SP 600125抑制VEGF诱导的血管生成。进一步的结果显示，SP 600125和JNK/SAPK siRNA降低了VEGF诱导的HUVECs中VEGFR 2（Flk-1/KDR）持续磷酸化。综上所述，所有这些结果表明JNK/SAPK调节VEGF诱导的VEGFR 2持续磷酸化，其在VEGF诱导的HUVECs血管生成中起重要作用。
c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is involved in the regulation of various cellular functions including cell cycle, proliferation, apoptosis. However, whether JNK/SAPK directly regulates the angiogenesis of human umbilical vein endothelial cells (HUVECs) induced by vascular endothelial growth factor A (VEGFA) has not yet been fully elucidated. Our present study firstly demonstrated VEGFA-induced angiogenic responses including the increase of cell viability, migration, and tube formation with a concentration-dependent manner in HUVECs. Further results showed that VEGFA induced the activation of JNK/SAPK, p38 kinase and extracellular signal-regulated kinases 1 and 2 (ERK1/2), while JNK/SAPK inhibitor SP600125 and specific siRNA both blocked all those angiogenic effects induced by VEGFA. Furthermore, VEGFA induced the phosphorylation of ASK1, SEK1/MKK4, MKK7, and c-Jun, which are upstream or downstream signals of JNK/SAPK. In addition, in vivo matrigel plug assay further showed that SP600125 inhibited VEGFA-induced angiogenesis. Further results showed that SP600125 and JNK/SAPK siRNA decreased VEGFA-induced VEGFR2 (Flk-1/KDR) sustained phosphorylation in HUVECs. Taken together, all these results demonstrate that JNK/SAPK regulates VEGFA-induced VEGFR2 sustained phosphorylation, which plays important roles in VEGFA-induced angiogenesis in HUVECs.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
4.5
作者：
Bruns, Alexander F.;Herbert, Shane P.;Ponnambalam, Sreenivasan
通讯作者：
Ponnambalam, Sreenivasan
DOI：
10.1016/s0021-9258(18)47116-5
发表时间：
1994-10
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
J. Waltenberger;L. Claesson-Welsh;Agneta Siegbahnll;M. Shibuya;Carl-Henrik HeldinS
通讯作者：
J. Waltenberger;L. Claesson-Welsh;Agneta Siegbahnll;M. Shibuya;Carl-Henrik HeldinS
影响因子：
4.3
作者：
M. Clauss;G. Breier
通讯作者：
M. Clauss;G. Breier
影响因子：
4.3
作者：
Lijian Hui;L. Bakiri;Ewa Stepniak;E. Wagner
通讯作者：
Lijian Hui;L. Bakiri;Ewa Stepniak;E. Wagner