TNF-related activation-induced cytokine (TRANCE) induces angiogenesis through the activation of Src and phospholipase C (PLC) in human endothelial cells.
Angiogenesis is an essential step for many physiological and pathological processes. Tumor necrosis factor (TNF) superfamily cytokines are increasingly recognized as key modulators of angiogenesis. In this study, we tested whether TNF-related activation-induced cytokine (TRANCE), a new member of the TNF superfamily, possesses angiogenic activity in vitro and in vivo. TRANCE stimulated DNA synthesis, chemotactic motility, and capillary-like tube formation in primary cultured human umbilical vein endothelial cells (HUVECs). Both Matrigel plug assay in mice and chick chorioallantoic membrane assay revealed that TRANCE potently induced neovascularization in vivo. TRANCE had no effect on vascular endothelial growth factor (VEGF) expression in HUVECs and TRANCE-induced angiogenic activity was not suppressed by VEGF-neutralizing antibody, implying that TRANCE-induced angiogenesis may be the result of its direct action on endothelial cells. TRANCE evoked a time- and dose-dependent activation of the mitogen-activated protein kinases ERK1/2 and focal adhesion kinase p125(FAK) in HUVECs, which are closely linked to angiogenesis. These signaling events were blocked by the Src inhibitor PP1 or the phospholipase C (PLC) inhibitor. Furthermore, these inhibitors and the Ca(2+) chelator BAPTA-AM suppressed TRANCE-induced HUVEC migration. These results indicate that the angiogenic activity of TRANCE is mediated through the Src-PLC-Ca(2+) signaling cascade upon receptor engagement in endothelial cells, suggesting the role of TRANCE in neovessel formation under physiological and pathological conditions.
Kim
Young-Mi
YM
Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon, Kangwon-Do 200-701, Korea.
Kim
Young-Myoung
YM
Lee
You Mie
YM
Kim
Hae-Sun
HS
Kim
Jong Dai
JD
Choi
Yongwon
Y
Kim
Kyu-Won
KW
Lee
Soo-Young
SY
Kwon
Young-Guen
YG
D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry*; D002465:Cell Movement; D002478:Cells, Cultured; D003094:Collagen / Q000737:chemistry; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D016228:Endothelial Growth Factors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D007797:Laminin / Q000737:chemistry; D008222:Lymphokines / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000737:chemistry*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009389:Neovascularization, Pathologic; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011509:Proteoglycans / Q000737:chemistry; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D002352:Carrier Proteins; D004338:Drug Combinations; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D004963:Estrenes; D007797:Laminin; D008222:Lymphokines; D008562:Membrane Glycoproteins; D010726:Phosphodiesterase Inhibitors; D011509:Proteoglycans; D011760:Pyrrolidinones; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C059485:matrigel; D003094:Collagen; D004247:DNA; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D016392:Proto-Oncogene Proteins pp60(c-src); D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D002118:Calcium