© 1999 American Heart Association, Inc.
Vascular Biology |
Angiotensin II Stimulates Collagen Synthesis in Human Vascular Smooth Muscle Cells
Involvement of the AT1 Receptor, Transforming Growth Factor-ß, and Tyrosine Phosphorylation
From the John P. Robarts Research Institute, Vascular Biology Group, and London Health Sciences Centre, Departments of Medicine (Cardiology), Biochemistry, and Medical Biophysics, University of Western Ontario, London, Ontario, Canada.
Correspondence to J. Geoffrey Pickering, London Health Sciences Centre, 339 Windermere Rd, London, Ontario, Canada N6A 5A5. E-mail gpickrng{at}rri.on.ca
Abstract—Angiotensin
II is an established regulator of vascular tone and smooth muscle cell
(SMC) growth. However, there are little data about its effect on
collagen synthesis by SMCs and none regarding the mechanism of such an
effect. We studied the effect of angiotensin II on collagen
production by human arterial SMCs, using uptake of
[3H]proline into collagenase-digestible
proteins, and by ribonuclease protection assay for mRNA encoding the
pro
1 chain of type I collagen, the major collagen in arteries. This
revealed a dose-dependent increase in relative collagen synthesis rate
and a dose-dependent increase in pro1(I) collagen mRNA abundance,
with the half-maximal effect at 1.7 nmol/L. Angiotensin
II–stimulated collagen expression was associated with a 6-fold
increase in transforming growth factor-ß (TGF-ß) production
and was inhibited by a neutralizing antibody to TGF-ß. Both collagen
production and TGF-ß release were inhibited by the
AT1-specific antagonist, losartan, but
not by the AT2 receptor antagonist, PD123319.
To determined if tyrosine phosphorylation was
functionally linked to collagen synthesis, we studied the effect of 2
mechanistically distinct inhibitors of tyrosine kinase,
genistein, and tyrphostin A25. These inhibitors abrogated
angiotensin II–mediated procollagen mRNA expression and
angiotensin II–mediated TGF-ß production,
whereas the inactive homolog tyrphostin A1 had no effect. We conclude
that angiotensin II stimulates collagen production
in human arterial SMCs via the AT1 receptor and
an autocrine loop of TGF-ß, induction of which requires tyrosine
phosphorylation.
Key Words: angiotensin • smooth muscle cell • collagen • tyrosine kinase • transforming growth factor
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