© 1997 American Heart Association, Inc.
Articles |
Platelet-Derived Growth Factor ß-Receptors Can Both Promote and Inhibit Chemotaxis in 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 Gerard Clunn, Department of Clinical Pharmacology, Imperial College School of Medicine at St Mary's, South Wharf Rd, Paddington, London, W2 1NY, UK. E-mail g.clunn{at}ic.ac.uk
Abstract The effect of the three platelet-derived growth
factor (PDGF) isoforms AA, AB, and BB on migration was investigated in
cultured human saphenous vein smooth muscle cells. The modified Boyden
chamber technique yielded efficacies BB>>AB, AA=0. However,
the BB concentration-response relationship displayed a pronounced peak,
occurring between 1 and 10 ng/mL, with no response above this range.
Checkerboard analysis showed that the promotion of migration at
low concentrations was chemotactic in nature but that the downturn was
independent of gradient. Furthermore, at high concentrations BB was
able to prevent chemotaxis induced by fetal calf serum and epidermal
growth factor (EGF). Experiments using low concentrations of BB in
combination with high concentrations of AA to saturate PDGF
-receptors in the presence and absence of a neutralizing antibody to
-receptors revealed that -receptor activation induced partial
inhibition of chemotaxis but this did not account for the inhibition of
migration by high concentrations of BB. Despite possessing no
significant chemotactic action itself, high concentrations of the AB
isoform completely inhibited BB induced chemotaxis. Taken together
these results suggest that the chemotactic signal induced by PDGF is
dominated by PDGF ß-receptors and switches from positive at low
concentrations to negative at higher concentrations. Stimulation of DNA
synthesis by the three isoforms (as measured by [3H]
thymidine incorporation) yielded saturable responses for the AB and BB
isoforms, with similar efficacy and weak or no response for the AA
isoform. Concentration-dependent patterns of tyrosine
phosphorylation of certain proteins mirrored the form
of the chemotactic response and suggest one possible underlying
regulatory mechanism to account for the disparity between PDGF-induced
chemotaxis and DNA synthesis.
Key Words: vascular smooth muscle • platelet-derived growth factor • chemotaxis • tyrosine phosphorylation
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