title: Different activation forms of MMP-2 oppositely affect the fate of endothelial cells.
abstract: Detachment of endothelial cells (ECs) from the extracellular matrix (ECM) is required not only for angiogenesis, but also for EC apoptosis. Matrix metalloproteinase (MMP)-2 plays a major role in the degradation of the ECM, supporting an essential role for this enzyme in both survival (angiogenesis) and death of ECs. Our aim was to study these seemingly paradoxical effects of MMP-2. We rationalized that inhibiting apoptosis would drive MMP-2 toward a prosurvival activity, clarifying the mechanisms involved. By employing specific inhibitors to two major apoptotic pathways in ECs, caspases and p38 MAPK (p38), we demonstrated that they differently affected EC behavior as well as MMP-2 expression. The p38 pathway appears to enhance MMP-2 synthesis, its partial ("intermediate") and its full activation, probably via membrane type (MT)1-MMP, while caspases enhance MMP-2 synthesis and full activation but reduce MT1-MMP and MMP-2 intermediate form. Evaluation of the reciprocal influences of MMP-2 on ECs showed that the intermediate form supported survival and migration, and the fully active form led to cell death. In addition, a pro- and intermediate form-rich environment, even in the presence of the fully active form, exerted protective effects. Thus the seemingly conflicting effects of MMP-2 on EC survival may be explained by the ratio between the MMP-2 activation forms. A regulatory loop between active MMP-2 and p38 but not between MMP-2 and caspases was also observed, suggesting that MMP-2 is downstream to caspases where it serves as an "exterminator" molecule. Altogether, modification of caspase and p38 pathways, via changes of local MMP-2, affect survival and angiogenic steps in ECs.
authors.affiliation: Immunology Research Unit, Carmel Medical Center, 7 Michal St., Haifa 34362, Israel.
authors.forename: Sarah
authors.initials: S
authors.lastname: Shapiro
authors.forename: Olga
authors.initials: O
authors.lastname: Khodalev
authors.forename: Haim
authors.initials: H
authors.lastname: Bitterman
authors.forename: Ron
authors.initials: R
authors.lastname: Auslender
authors.forename: Nitza
authors.initials: N
authors.lastname: Lahat
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors; D002465:Cell Movement / Q000502:physiology; D048430:Cell Shape; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2; C093642:SB 203580