Dual role for TWEAK in angiogenic regulation.
Angiogenic regulators modulate endothelial cell functions, including proliferation, migration, secretion, and adhesion, through their action on endothelial cells or other cell types. TWEAK, a novel member of the tumor necrosis factor family, appears to be a pro-angiogenic agent on the basis of previous studies demonstrating its ability to induce interleukin-8 production by epithelial tumor lines, stimulate proliferation of human vascular cell types and neovascularization in rat corneas. Here, we further characterized the angiogenic potential of TWEAK, revealing a dual role for TWEAK as an angiogenic regulator. We demonstrate that TWEAK is a potent inducer of endothelial cell survival and cooperates with basic fibroblast growth factor to induce the proliferation and migration of human endothelial cells and morphogenesis of capillary lumens. In contrast, TWEAK antagonizes the morphogenic response of endothelial cells to vascular endothelial growth factor (VEGF) without inhibiting VEGF-induced survival or proliferation. Thus, our observations suggest that TWEAK may differentially regulate microvascular growth, remodeling and/or maintenance in vivo, depending upon the angiogenic context.
Jakubowski
Aniela
A
Department of Exploratory Science, Biogen Inc., 12 Cambridge Center, Cambridge, Massachusetts 02142, USA. Aniela_Jakubowski@Biogen.com
Browning
Beth
B
Lukashev
Matvey
M
Sizing
Irene
I
Thompson
Jeffrey S
JS
Benjamin
Christopher D
CD
Hsu
Yen-Ming
YM
Ambrose
Christine
C
Zheng
Timothy S
TS
Burkly
Linda C
LC
D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002196:Capillaries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000819:agonists / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D048069:Tumor Necrosis Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D000074049:Cytokine TWEAK; D016228:Endothelial Growth Factors; D008222:Lymphokines; C109743:TNFSF12 protein, human; D048069:Tumor Necrosis Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2