© 1997 American Heart Association, Inc.
Articles |
Thrombospondin-1 Is a Potent Mitogen and Chemoattractant for Human Vascular Smooth Muscle Cells
From the Department of Clinical Pharmacology, Imperial College School of Medicine at St Mary's, London, UK.
Correspondence to Dr Mahendra Patel, Department of Clinical Pharmacology, Imperial College School of Medicine at St Mary's, St Mary's Hospital, London W2 1NY, England UK. E-mail m.k.patel{at}ic.ac.uk
Abstract Thrombospondin-1 (TSP-1) is a matricellular protein
that is present in negligible amounts in normal human vasculature
but occurs in significant amounts in diseased vessels. In this study,
we examined the effect of TSP-1 on DNA synthesis, proliferation, and
migration in human vascular smooth muscle cells grown from saphenous
vein. TSP-1 (0.1 to 30 µg/mL) elicited a concentration-dependent
increase in DNA synthesis under serum-free conditions. In combination
with platelet-derived growth factor, TSP-1 induced a synergistic
effect on DNA synthesis that was significantly higher than the additive
effect of both agents. In proliferation assays, TSP-1 increased cell
numbers by 50% relative to the serum-free controls over 14 days. In
migration assays, conducted using modified Boyden chambers, TSP-1 (
10
µg/mL) elicited marked chemotaxis to a degree equivalent to
platelet-derived growth factor. The chemotactic response to TSP-1
(10 µg/mL) was abolished by the GRGDSP peptide but unaffected by the
control GRGESP peptide, whereas neither peptide inhibited DNA synthesis
stimulated by TSP-1. Inhibition of tyrosine kinase activity with
genistein or tyrphostin A23 abolished DNA synthesis induced by TSP-1,
and a neutralizing antibody to platelet-derived growth factor had
no effect on DNA synthesis. Similarly, migration in response to TSP-1
was largely inhibited by these tyrosine kinase inhibitors.
TSP-1 is a strong mitogen and chemoattractant for human vascular smooth
muscle cells under serum-free conditions. The novel finding that TSP-1
is mitogenic for human cells contrasts with previous
studies that have not shown any significant effect of TSP-1 itself on
the growth of animal-derived smooth muscle cells. TSP-1 may play an
important modulatory role in the local regulation of vascular smooth
muscle function in vascular pathologies in humans.
Key Words: thrombospondin-1 • DNA synthesis • proliferation • migration • human vascular smooth muscle
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