Ren Juan, Zhang Yuelang, Cai Hui, Ma Hongbing, Zhao Dongli, Zhang Xiaozhi, Li Zongfang, Wang Shufeng, Wang Jiangsheng, Liu Rui, Li Yi, Qian Jiansheng, Wei Hongxia, Niu Liying, Liu Yan, Xiao Lisha, Ding Muyang, Jiang Shiwen
Department of Radiotherapy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Imaging Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Mol Med Rep. 2016 Aug;14(2):1235-40. doi: 10.3892/mmr.2016.5380. Epub 2016 Jun 9.
G protein-coupled receptor 4 (GPR4) is hypothesized to function as a pH sensor and is important in the regulation of proliferation, migration and angiogenesis of vascular endothelial cells (ECs). Furthermore, the Notch signaling pathway is significant in the regulation of the angiogenic behavior of ECs. However, whether GPR4 regulates angiogenesis via the Notch signaling pathway remains unclear. The present study evaluated the effect of Notch signaling in human GPR4‑induced angiogenesis in HMEC‑1 cells. The results revealed that GPR4 increased Notch1 expression in a time‑dependent manner. In addition, the inhibition of Notch1 expression using small interfering RNA or the Notch receptor inhibitor, γ-secretase inhibitor I, significantly blocked GPR4‑induced HMEC‑1 tube formation and lymphocyte transendothelial migration. Furthermore, the inhibition of Notch1 blocked GPR4‑induced vascular endothelial growth factor and hypoxia-inducible factor 1α expression. Thus, it was demonstrated that GPR4 affects ECs by regulating Notch1, a function that may be important for physiological and pathological angiogenesis.
G蛋白偶联受体4（GPR4）被推测作为一种pH传感器发挥作用，并且在调节血管内皮细胞（ECs）的增殖、迁移和血管生成中起重要作用。此外，Notch信号通路在调节ECs的血管生成行为中具有重要意义。然而，GPR4是否通过Notch信号通路调节血管生成仍不清楚。本研究评估了Notch信号在人GPR4诱导的HMEC-1细胞血管生成中的作用。结果显示，GPR4以时间依赖性方式增加Notch1表达。此外，使用小干扰RNA或Notch受体抑制剂γ-分泌酶抑制剂I抑制Notch1表达，可显著阻断GPR4诱导的HMEC-1管形成和淋巴细胞跨内皮迁移。此外，抑制Notch1可阻断GPR4诱导的血管内皮生长因子和缺氧诱导因子1α表达。因此，证明了GPR4通过调节Notch1影响ECs，这一功能可能对生理和病理血管生成具有重要意义。
