© 1997 American Heart Association, Inc.
Articles |
Coordinated Effects of Fibroblast Growth Factor-2 on Expression of Fibrillar Collagens, Matrix Metalloproteinases, and Tissue Inhibitors of Matrix Metalloproteinases by Human Vascular Smooth Muscle Cells
Evidence for Repressed Collagen Production and Activated Degradative Capacity
From the John P. Robarts Research Institute and London Health Sciences Centre, Department of Medicine (Cardiology), Medical Biophysics, and Biochemistry, University of Western Ontario, London, Canada.
Correspondence to J. Geoffrey Pickering, London Health Sciences Centre, 339 Windermere Rd, London, Ontario N6A 5A5, Canada. E-mail gpickrng{at}rri.uwo.ca
Abstract Fibroblast growth factor-2 (FGF-2) is an established
mediator of smooth muscle cell (SMC) proliferation after vascular
injury. However, the influence of FGF-2 on collagen fiber remodeling,
which may be a prerequisite for vascular SMC accumulation, is not well
understood. We determined that FGF-2 almost completely abrogated the
formation of immunodetectable type I collagen fibers in the
extracellular matrix of cultured human vascular SMCs. This was
associated with reduced expression of pro
-chains for types I and III
collagen, as assessed by Western blot analysis, and a corresponding
reduction in collagen synthesis. Densitometry of Northern blots
indicated a potent reduction of mRNA encoding pro-chains for types I
and III collagen and a minor reduction in mRNA for pro-chains for
type V collagen. Interstitial collagenase (MMP-1), which is required
for degradation of collagen types I and III, was not expressed by SMCs
under basal culture conditions, but expression was induced by FGF-2,
with a potent, dose-dependent increase in MMP-1 protein in conditioned
medium. Metalloproteinase inhibitors TIMP-1, TIMP-2, and TIMP-3 were
expressed by unstimulated SMCs and were differentially regulated by
FGF-2. TIMP-1 expression increased modestly, TIMP-2 expression was
repressed, and TIMP-3 was relatively unaffected. The net effect on
substrate degradation, as assessed by zymography of conditioned media,
was induction of MMP-1 lytic activity by FGF-2, with no effect on the
activity of MMP-2, MMP-3, or MMP-9. These data indicate that
stimulation of human SMCs with FGF-2 establishes a phenotype in which
collagen fiber production is repressed and the capacity for fiber
degradation activated. This coordinated response may be critical for
SMC accumulation during vascular remodeling as well as atherosclerotic
plaque destabilization.
Key Words: smooth muscle cells • fibroblast growth factor • collagen • metalloproteinase
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