Tumor necrosis factor and vascular endothelial growth factor induce endothelial integrin repertories, regulating endovascular differentiation and apoptosis in a human extravillous trophoblast cell line.
Angiogenesis is crucial in human development. Extravillous trophoblast (EVT) cells mimic endothelial cells in angiogenesis during endovascular differentiation, inducing a remodeling of spiral arteries that increases blood flow toward the intravillous space. We have previously shown that tumor necrosis factor (TNF) alpha regulates expression of ITGA6 and ITGA1, which are involved in cell survival, in the human EVT cell line TCL1. To further investigate endovascular differentiation, we examined the effects of vascular endothelial growth factor (VEGF), TNF, and extracellular matrix (ECM) on TCL1 cells. Seeded on Matrigel, TCL1 cells show tube-like formation that specifically recalls morphological changes in endothelial cells. Anti-ITGAV/ITGB3 antibodies significantly reduced the size of the capillary network (P < 0.05) on Matrigel and also suppressed TNF-induced apoptosis (P < 0.05) in TCL1 cells. VEGF induced expression of ITGAV/ITGB3 subunits and protein aggregation, as in the case of TNF, which in turn, induces synthesis of VEGF in TCL1 cells. Soluble FLT1 suppressed these activities in TCL1 cells, indicating that signals involving VEGF axis are essential for endovascular differentiation. These results suggest that TNF, VEGF, and ECM collaboratively regulate EVT behavior, including cell survival and endovascular differentiation, through integrin signaling during establishment and maintenance of successful human pregnancies.
Fukushima
Kotaro
K
Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. kfuku@gynob.med.kyushu-u.ac.jp
Miyamoto
Shingo
S
Tsukimori
Kiyomi
K
Kobayashi
Hiroaki
H
Seki
Hiroyuki
H
Takeda
Satoru
S
Kensuke
Egashira
E
Ohtani
Kishio
K
Shibuya
Masabumi
M
Nakano
Hitoo
H
D017209:Apoptosis / Q000502:physiology; D002452:Cell Count; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D003094:Collagen; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology* / Q000502:physiology; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics / Q000502:physiology*; D039641:Integrin beta Chains / Q000235:genetics / Q000502:physiology*; D007797:Laminin; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011247:Pregnancy; D011506:Proteins / Q000494:pharmacology; D011509:Proteoglycans; D014162:Transfection; D014327:Trophoblasts / Q000166:cytology* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1
D004338:Drug Combinations; D039001:Integrin alpha Chains; D039641:Integrin beta Chains; D007797:Laminin; D011506:Proteins; D011509:Proteoglycans; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1