Human GPR4 and the Notch signaling pathway in endothelial cell tube formation.
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.
Department of Radiotherapy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Juan
J
Ren
Imaging Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Yuelang
Y
Zhang
Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Hui
H
Cai
Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Hongbing
H
Ma
Department of Radiotherapy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Dongli
D
Zhao
Department of Radiotherapy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Xiaozhi
X
Zhang
Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Zongfang
Z
Li
Department of Radiotherapy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Shufeng
S
Wang
Department of Radiotherapy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Jiangsheng
J
Wang
Department of Radiotherapy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Rui
R
Liu
Department of Radiotherapy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Yi
Y
Li
Department of Radiotherapy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Jiansheng
J
Qian
Department of Radiotherapy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Hongxia
H
Wei
Department of Radiotherapy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Liying
L
Niu
Department of Radiotherapy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Yan
Y
Liu
Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Lisha
L
Xiao
Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Muyang
M
Ding
Department of Biomedical Science, Mercer University School of Medicine, Macon, GA 31207, USA.
Shiwen
S
Jiang
D002460:Cell Line; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000235:genetics; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D057705:Transendothelial and Transepithelial Migration; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C091670:GPR4 protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D043562:Receptors, G-Protein-Coupled; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A