内皮干细胞
新生血管
细胞生物学
血管内皮生长因子
小干扰RNA
血管内皮生长因子A
生物
遗传增强
基因沉默
医学
作者
Ashraf-ul Kabir,Tae-Jin Lee,Hua Pan,Jeffrey C. Berry,Karen Krchma,Jun Wu,Fang Liu,Hee-Kyoung Kang,Kristina Hinman,Lihua Yang,Samantha L. Hamilton,Qingyu Zhou,Deborah J. Veis,Robert P. Mecham,Samuel A. Wickline,Mark J. Miller,Kyunghee Choi
出处
期刊:JCI insight
[American Society for Clinical Investigation]
日期:2018-04-19
卷期号:3 (8)
被引量:13
标识
DOI:10.1172/jci.insight.97349
摘要
Angiogenesis, new blood vessel formation from preexisting vessels, is critical for solid tumor growth. As such, there have been efforts to inhibit angiogenesis as a means to obstruct tumor growth. However, antiangiogenic therapy faces major challenges to the selective targeting of tumor-associated-vessels, as current antiangiogenic targets also disrupt steady-state vessels. Here, we demonstrate that the developmentally critical transcription factor Etv2 is selectively upregulated in both human and mouse tumor-associated endothelial cells (TAECs) and is required for tumor angiogenesis. Two-photon imaging revealed that Etv2-deficient tumor-associated vasculature remained similar to that of steady-state vessels. Etv2-deficient TAECs displayed decreased Flk1 (also known as Vegfr2) expression, FLK1 activation, and proliferation. Endothelial tube formation, proliferation, and sprouting response to VEGF, but not to FGF2, was reduced in Etv2-deficient ECs. ROS activated Etv2 expression in ECs, and ROS blockade inhibited Etv2 expression in TAECs in vivo. Systemic administration of Etv2 siRNA nanoparticles potently inhibited tumor growth and angiogenesis without cardiovascular side effects. These studies highlight a link among vascular oxidative stress, Etv2 expression, and VEGF response that is critical for tumor angiogenesis. Targeting the ETV2 pathway might offer a unique opportunity for more selective antiangiogenic therapies.
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