Membrane type 1-matrix metalloproteinase induces endothelial cell morphogenic differentiation by a caspase-dependent mechanism.
Membrane-type 1 matrix metalloproteinase (MT1-MMP) has been suggested to play an essential role in angiogenesis. Based on recent evidence suggesting that the sprouting and branching of capillaries during angiogenesis involves apoptosis, we investigated the involvement of this process in MT1-MMP-dependent morphogenic differentiation of EC into capillary-like structures. We found that MT1-MMP sensitizes EC to apoptosis, since reduction of MT1-MMP expression abolished vimentin fragmentation in apoptotic HUVECs while overexpression of the enzyme induced caspase-3 activity in BAECs subjected to pro-apoptotic treatments. MT1-MMP-mediated caspase-3 activation likely occurs through the mitochondrial pathway since it was abrogated by Bcl-2, but not by CrmA overexpression. Reduction of MT1-MMP expression in HUVECs reduced morphogenic differentiation that was correlated with diminished vimentin fragmentation, whereas its overexpression in BAECs stimulated both processes. Inactivation of the catalytic activity or removal of the cytoplasmic domain of MT1-MMP markedly reduced its ability to induce both morphogenic differentiation and caspase-3 activation. The inhibitory effects of the anti-apoptotic protein Bcl-2 and the caspase inhibitor zVAD-fmk further suggested the involvement of apoptosis during MT1-MMP-mediated morphogenic differentiation. Our results show that the ability of MT1-MMP to induce EC morphogenic differentiation involves its activation of a caspase-dependent mechanism.
Langlois
Stéphanie
S
Laboratoire de Médecine moléculaire, Hôpital Ste-Justine-Université du Québec à Montréal, Centre de Cancérologie Charles-Bruneau, 3175 Chemin Côte-Ste-Catherine, Montréal, Québec, Canada H3T 1C5.
Di Tomasso
Geneviève
G
Boivin
Dominique
D
Roghi
Christian
C
Murphy
Gillian
G
Gingras
Denis
D
Béliveau
Richard
R
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D020134:Catalytic Domain / Q000235:genetics; D002417:Cattle; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D014162:Transfection; D014746:Vimentin / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D014746:Vimentin; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases