Hypoxia-Inducible Factor-Dependent Expression of Angiopoietin-Like 4 by Conjunctival Epithelial Cells Promotes the Angiogenic Phenotype of Pterygia.
Hypoxia-Inducible Factor-Dependent Expression of Angiopoietin-Like 4 by Conjunctival Epithelial Cells Promotes the Angiogenic Phenotype of Pterygia.
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结膜上皮细胞缺氧诱导因子依赖性血管生成素样 4 的表达促进翼状胬肉的血管生成表型
DOI：
10.1167/iovs.17-21974
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发表时间：
2017-09-01
影响因子：
4.4
通讯作者：
Sodhi A
中科院分区：
文献类型：
--
作者：
Meng Q;Qin Y;Deshpande M;Kashiwabuchi F;Rodrigues M;Lu Q;Ren H;Elisseeff JH;Semenza GL;Montaner SV;Sodhi A
目的评估血管内皮生长因子（VEGF）治疗翼状胬肉疗效的临床研究结果令人失望，提示其他血管生成介质也可能在翼状胬肉的发展中发挥作用。因此，我们探讨了VEGF、缺氧诱导因子（HIF）-1α（在眼部新生血管疾病中调节VEGF表达的转录因子）和第二种HIF调节介质血管生成素样4（ANGPTL 4）对翼状胬肉血管生成表型的相对贡献。方法检测翼状胬肉组织、人永生化结膜上皮细胞（ih）和兔原代结膜上皮细胞（pr）中HIF-1α、VEGF和ANGPTL 4的表达。在存在或不存在靶向VEGF、ANGPTL 4或两者的HIF-1或RNA干扰（RNAi）的诱导剂/抑制剂的情况下，使用由ihCjEC调节的培养基的内皮细胞（EC）小管形成测定用于评估它们对这些细胞的血管生成潜力的相对贡献。结果6/6例手术切除的翼状胬肉组织中均有HIF-1α和VEGF表达，且定位于CjECs。HIF-1α在ihCjECs和prCjECs（包括在胶原玻璃胶上生长的分层的prCjECs）中的积累被证实，并导致VEGF的表达和EC小管形成的促进;后者的作用被靶向VEGF mRNA表达的RNAi部分阻断。我们证明了第二种HIF调节的血管生成介质ANGPTL 4在培养的CjEC和手术切除的翼状胬肉中的表达。靶向ANGPTL 4的RNAi抑制EC小管形成，并且是靶向VEGF的RNAi的添加剂。结论我们的研究结果支持开发靶向ANGPTL 4和VEGF的治疗翼状胬肉患者的疗法。
Purpose Disappointing results from clinical studies assessing the efficacy of therapies targeting vascular endothelial growth factor (VEGF) for the treatment of pterygia suggest that other angiogenic mediators may also play a role in its development. We therefore explore the relative contribution of VEGF, hypoxia-inducible factor (HIF)-1α (the transcription factor that regulates VEGF expression in ocular neovascular disease), and a second HIF-regulated mediator, angiopoietin-like 4 (ANGPTL4), to the angiogenic phenotype of pterygia. Methods Expression of HIF-1α, VEGF, and ANGPTL4 were examined in surgically excised pterygia, and in immortalized human (ih) and primary rabbit (pr) conjunctival epithelial cells (CjECs). Endothelial cell (EC) tubule formation assays using media conditioned by ihCjECs in the presence or absence of inducers/inhibitors of HIF-1 or RNA interference (RNAi) targeting VEGF, ANGPTL4, or both were used to assess their relative contribution to the angiogenic potential of these cells. Results HIF-1α and VEGF expression were detected in 6/6 surgically excised pterygia and localized to CjECs. Accumulation of HIF-1α in was confirmed in ihCjECs and prCjECs, including stratified prCjECs grown on collagen vitrigel, and resulted in expression of VEGF and the promotion of EC tubule formation; the latter effect was partially blocked using RNAi targeting VEGF mRNA expression. We demonstrate expression of a second HIF-regulated angiogenic mediator, ANGPTL4, in CjECs in culture and in surgically excised pterygia. RNAi targeting ANGPTL4 inhibited EC tubule formation and was additive to RNAi targeting VEGF. Conclusions Our results support the development of therapies targeting both ANGPTL4 and VEGF for the treatment of patients with pterygia.
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影响因子：
4.2
作者：
HILGERS, JHC
通讯作者：
HILGERS, JHC
影响因子：
2.8
作者：
Hu, Qiongwen;Qiao, Yanbing;Ma, Yongping
通讯作者：
Ma, Yongping
影响因子：
13.7
作者：
Kaufman, Stephen C.;Jacobs, Deborah S.;Shtein, Roni M.
通讯作者：
Shtein, Roni M.
影响因子：
2.8
作者：
Ozgurhan, Engin B.;Agca, Alper;Demirok, Ahmet
通讯作者：
Demirok, Ahmet
影响因子：
4.8
作者：
Perdiguero, Elisa Gomez;Galaup, Ariane;Germain, Stephane
通讯作者：
Germain, Stephane