Platelet-activating factor (PAF) induces activation of matrix metalloproteinase 2 activity and vascular endothelial cell invasion and migration.
Tumor-induced angiogenic responses lead to complex phenotypic changes in vascular endothelial cells, which must coordinate the expression of both proteases and protease inhibitors prior to the proliferation and invasion of surrounding stroma. Matrix metalloproteinase 2 (MMP2), which degrades Type IV collagen, is produced as proMMP2. proMMP2 is activated in part through its interactions with membrane Type 1 MMP (MT1-MMP) and tissue inhibitor of matrix metalloproteinase 2 (TIMP2). In this study, we demonstrate that platelet-activating factor (PAF) is a potent inducer of human umbilical vein endothelial cell (HUVEC) migration and invasion, which is attenuated by PAF receptor antagonists, and that PAF receptor antagonists inhibit the migration and invasion of HUVEC mediated by medium conditioned by a prostatic carcinoma cell line. We confirm that PAF receptor antagonists inhibit proliferation of HUVEC grown in rich growth medium. We show that PAF increases mRNA levels for MT1-MMP and TIMP2, followed by increased temporal conversion of latent proMMP2 to MMP2. Finally, we demonstrate that the ratio of MT1-MMP to TIMP2 in membrane preparations from PAF-stimulated HUVEC is 1.6:1, approximating the hypothesized ideal ratio of 2:1 necessary for the conversion of proMMP2 to MMP2. Our data support the involvement of PAF in vascular endothelial cell migration and invasion.
Axelrad
T William
TW
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Deo
Dayanand D
DD
Ottino
Paulo
P
Van Kirk
Jennefer
J
Bazan
Nicolas G
NG
Bazan
Haydee E P
HE
Hunt
Jay D
JD
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000235:genetics; D010972:Platelet Activating Factor / Q000494:pharmacology* / Q000502:physiology; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D015290:Second Messenger Systems / Q000502:physiology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis / Q000235:genetics; D014471:Umbilical Veins
D017077:Culture Media, Conditioned; D004792:Enzyme Precursors; D006133:Growth Substances; D008565:Membrane Proteins; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D019716:Tissue Inhibitor of Metalloproteinase-2; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2