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)

Giuseppe Pintucci, Pey Jen Yu, Ram Sharony, F. Gregory Baumann, Fiorella Saponara, Antonio Frasca, Aubrey C. Galloway, David Moscatelli, Paolo Mignatti

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1015-1025
Number of pages11
JournalJournal of Cellular Biochemistry
Volume90
Issue number5
DOIs
StatePublished - 1 Dec 2003
Externally publishedYes

Keywords

  • Endothelial cells
  • Fibroblast growth factors
  • Matrix-metalloproteinases
  • Signal transduction

Fingerprint

Dive into the research topics of '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)'. Together they form a unique fingerprint.

Cite this