Human GPR4 and the Notch signaling pathway in endothelial cell tube formation

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

doi:10.3892/mmr.2016.5380

Human GPR4 and the Notch signaling pathway in endothelial cell tube formation

Authors:
- Juan Ren
- Yuelang Zhang
- Hui Cai
- Hongbing Ma
- Dongli Zhao
- Xiaozhi Zhang
- Zongfang Li
- Shufeng Wang
- Jiangsheng Wang
- Rui Liu
- Yi Li
- Jiansheng Qian
- Hongxia Wei
- Liying Niu
- Yan Liu
- Lisha Xiao
- Muyang Ding
- Shiwen Jiang
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Affiliations: 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, Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China, Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China, Department of Biomedical Science, Mercer University School of Medicine, Macon, GA 31207, USA
Published online on: June 9, 2016 https://doi.org/10.3892/mmr.2016.5380
Pages: 1235-1240

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Abstract

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.

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