BET Bromodomain Suppression Inhibits VEGF-induced Angiogenesis and Vascular Permeability by Blocking VEGFR2-mediated Activation of PAK1 and eNOS

被引：46

作者：

Huang, Mingcheng ^{[1
]}

Qiu, Qian ^{[1
]}

Xiao, Youjun ^{[1
]}

Zeng, Shan ^{[1
]}

Zhan, Mingying ^{[2
]}

Shi, Maohua ^{[1
]}

Zou, Yaoyao ^{[1
]}

Ye, Yujin ^{[1
]}

Liang, Liuqin ^{[1
]}

Yang, Xiuyan ^{[1
]}

Xu, Hanshi ^{[1
]}

机构：

[1] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Rheumatol, Guangzhou 510275, Guangdong, Peoples R China

[2] Cent South Univ, Xiangya Med Sch, Dept Anesthesia, Changsha, Hunan, Peoples R China

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

基金：

中国国家自然科学基金;

关键词：

NITRIC-OXIDE SYNTHASE; SELECTIVE-INHIBITION; P21-ACTIVATED KINASE; IN-VIVO; INFLAMMATION; DISRUPTION; EXPRESSION; MIGRATION; PROTEINS; BRD4;

D O I：

10.1038/srep23770

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The tyrosine kinase receptor vascular endothelial growth factor receptor 2 (VEGFR2) is a critical modulator of angiogenesis. Increasing evidence indicate the important role of bromodomain and extraterminal domain (BET) of chromatin adaptors in regulating tumor growth and inflammatory response. However, whether BET proteins have a role in angiogenesis and endothelial permeability is unclear. In this study, we observed that treatment with JQ1, a specific BET inhibitor, suppressed in vitro tube formation of human umbilical vein endothelial cells (HUVECs) and in vivo angiogenesis in a Matrigel plug and oxygen-induced retinopathy neovascularization. JQ1 attenuated the VEGF-induced decrease in TEER in HUVECs and prevented Evans blue dye leakage in the VEGF-induced Miles assay in athymic Balb/c nude mice. BET inhibition with JQ1 or shRNA for Brd2 or Brd4 suppressed VEGF-induced migration, proliferation, and stress fiber formation of HUVECs. Furthermore, BET inhibition suppressed phosphorylation of VEGFR2 and PAK1, as well as eNOS activation in VEGF-stimulated HUVECs. Inhibition with VEGFR2 and PAK1 also reduced migration and proliferation, and attenuated the VEGFinduced decrease in TEER. Thus, our observations suggest the important role of BET bromodomain in regulating VEGF-induced angiogenesis. Strategies that target the BET bromodomain may provide a new therapeutic approach for angiogenesis-related diseases.

引用

页数：13

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