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)

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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.

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