Role of shear-stress-induced VEGF expression in endothelial cell survival
Role of shear-stress-induced VEGF expression in endothelial cell survival
复制标题
DOI：
10.1242/jcs.084301
复制
发表时间：
2012-02-15
影响因子：
4
通讯作者：
D'Amore, Patricia A.
中科院分区：
文献类型：
--
作者：
dela Paz, Nathaniel G.;Walshe, Tony E.;D'Amore, Patricia A.
血管内皮生长因子（VEGF）在发育性和病理性血管生成中起着至关重要的作用。VEGF在静止的成人组织中的表达表明在成熟血管的维持中具有潜在的作用。我们证明，使用Vegf-lacZ报告小鼠模型，血管内皮生长因子表达的动脉，但不是由静脉或毛细血管内皮细胞（EC）在体内。使用体外模型，我们表明，动脉切应力的人脐静脉内皮细胞（HUVECs）的细胞凋亡减少，并增加VEGF的表达，这是介导的诱导Kruppel样因子2（KLF 2）。此外，剪切应力刺激VEGF受体2（VEGFR 2）的表达，并与其活化相关。在剪切应力HUVECs中VEGF的敲低阻断了剪切应力的保护作用，导致EC凋亡相当于在静态条件下培养的对照EC中的凋亡。类似地，用VEGF受体酪氨酸激酶抑制剂SU 1498或VEGFR 2中和抗血清处理经受动脉剪切应力的EC导致细胞凋亡增加，表明机械保护免受剪切力增加是由VEGFR 2介导的。总之，这些研究表明，动脉血流诱导VEGF-VEGFR 2自分泌-β-肾上腺素信号，这是一个以前未确定的机制，血管EC存活在成人动脉血管。
Vascular endothelial growth factor (VEGF) plays a crucial role in developmental and pathological angiogenesis. Expression of VEGF in quiescent adult tissue suggests a potential role in the maintenance of mature blood vessels. We demonstrate, using a Vegf-lacZ reporter mouse model, that VEGF is expressed by arterial but not by venous or capillary endothelial cells (ECs) in vivo. Using an in vitro model, we show that arterial shear stress of human umbilical vein ECs (HUVECs) decreases apoptosis and increases VEGF expression, which is mediated by the induction of Kruppel-like factor 2 (KLF2). Additionally, shear stress stimulates the expression of VEGF receptor 2 (VEGFR2) and is associated with its activation. Knockdown of VEGF in shear stressed HUVECs blocks the protective effect of shear stress, resulting in EC apoptosis equivalent to that in control ECs cultured under static conditions. Similarly, treatment of ECs subjected to arterial shear stress with the VEGF receptor tyrosine kinase inhibitor SU1498, or VEGFR2 neutralizing antiserum, led to increased apoptosis, demonstrating that the mechanoprotection from increased shear is mediated by VEGFR2. Taken together, these studies suggest that arterial flow induces VEGF-VEGFR2 autocrine-juxtacrine signaling, which is a previously unidentified mechanism for vascular EC survival in adult arterial blood vessels.