Meng Qianli, Qin Yaowu, Deshpande Monika, Kashiwabuchi Fabiana, Rodrigues Murilo, Lu Qiaozhi, Ren Hui, Elisseeff Jennifer H, Semenza Gregg L, Montaner Silvia V, Sodhi Akrit
Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.
Guangdong Eye Institute, Department of Ophthalmology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou Guangdong, China.
Invest Ophthalmol Vis Sci. 2017 Sep 1;58(11):4514-4523. doi: 10.1167/iovs.17-21974.
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.
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.
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.
Our results support the development of therapies targeting both ANGPTL4 and VEGF for the treatment of patients with pterygia.
评估靶向血管内皮生长因子（VEGF）治疗翼状胬肉疗效的临床研究结果令人失望，这表明其他血管生成介质可能也在其发展过程中发挥作用。因此，我们探讨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）以及另一种受HIF调节的介质血管生成素样4（ANGPTL4）对翼状胬肉血管生成表型的相对贡献。
检测手术切除的翼状胬肉以及永生化人（ih）和原代兔（pr）结膜上皮细胞（CjECs）中HIF-1α、VEGF和ANGPTL4的表达。使用在有或无HIF-1诱导剂/抑制剂的情况下由ihCjECs条件培养基进行的内皮细胞（EC）小管形成试验，或针对VEGF、ANGPTL4或两者的RNA干扰（RNAi），来评估它们对这些细胞血管生成潜力的相对贡献。
在6/6例手术切除的翼状胬肉中检测到HIF-1α和VEGF表达，并定位于CjECs。在ihCjECs和prCjECs中证实了HIF-1α的积累，包括在胶原玻璃体上生长的分层prCjECs，这导致了VEGF的表达并促进了EC小管形成；使用靶向VEGF mRNA表达的RNAi可部分阻断后一种效应。我们证明了另一种受HIF调节的血管生成介质ANGPTL4在培养的CjECs和手术切除的翼状胬肉中的表达。靶向ANGPTL4的RNAi抑制了EC小管形成，并且与靶向VEGF的RNAi具有相加作用。
我们的结果支持开发同时靶向ANGPTL4和VEGF的疗法来治疗翼状胬肉患者。
