Induction of stromelysin-1 (MMP-3) by fibroblast growth factor-2 (FGF-2) in FGF-2-/- microvascular endothelial cells requires prolonged activation of extracellular signal-regulated kinases-1 and -2 (ERK-1/2).
Basic fibroblast growth factor (FGF-2) and matrix metalloproteinases (MMPs) play key roles in vascular remodeling. Because FGF-2 controls a number of proteolytic activities in various cell types, we tested its effect on vascular endothelial cell expression of MMP-3 (stromelysin-1), a broad-spectrum proteinase implicated in coronary atherosclerosis. Endothelial cells (EC) from FGF-2-/- mice are highly responsive to exogenous FGF-2 and were therefore used for this study. The results showed that treatment of microvascular EC with human recombinant FGF-2 results in strong induction of MMP-3 mRNA and protein expression. Upregulation of MMP-3 mRNA by FGF-2 requires de novo protein synthesis and activation of the ERK-1/2 pathway. FGF-2 concentrations (5-10 ng/ml) that induce rapid and prolonged (24 h) activation of ERK-1/2 upregulate MMP-3 expression. In contrast, lower concentrations (1-2 ng/ml) that induce robust but transient (<8 h) ERK-1/2 activation are ineffective. Inhibition of ERK-1/2 activation at different times (-0.5 h to +8 h) of EC treatment with effective FGF-2 concentrations blocks MMP-3 upregulation. Thus, FGF-2 induces EC expression of MMP-3 with a threshold dose effect that requires sustained activation of the ERK-1/2 pathway. Because FGF-2 controls other EC functions with a linear dose effect, these features indicate a unique role of MMP-3 in vascular remodeling.
Pintucci
Giuseppe
G
The Seymour Cohn Cardiovascular Surgery Research Laboratory, New York University School of Medicine, New York, New York 10016, USA. pintug01@med.nyu.edu
Yu
Pey-Jen
PJ
Sharony
Ram
R
Baumann
F Gregory
FG
Saponara
Fiorella
F
Frasca
Antonio
A
Galloway
Aubrey C
AC
Moscatelli
David
D
Mignatti
Paolo
P
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015854:Up-Regulation
D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019278:Matrix Metalloproteinase 3