PLATELET-DERIVED GROWTH-FACTOR BETA-RECEPTORS CAN BOTH PROMOTE AND INHIBIT CHEMOTAXIS IN HUMAN VASCULAR SMOOTH-MUSCLE CELLS

The effect of the three platelet-derived growth factor (PDGF) isoforms AA, AB, and BE on migration was investigated in cultured human saphen ous vein smooth muscle cells. The modified Boyden chamber technique yi elded efficacies BB much greater than AB, AA=0. However, the BE concen tration-response relationship displayed a pronounced peak, occurring b etween 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 gr adient. Furthermore, at high concentrations BE was able to prevent che motaxis induced by fetal calf serum and epidermal growth factor (EGF). Experiments using low concentrations of BE in combination with high c oncentrations of AA to saturate PDGF alpha-receptors in the presence a nd absence of a neutralizing antibody to alpha-receptors revealed that alpha-receptor activation induced partial inhibition of chemotaxis bu t this did not account for the inhibition of migration by high concent rations of BE. Despite possessing no significant chemotactic action it self, high concentrations of the AB isoform completely inhibited BE in duced chemotaxis. Taken together these results suggest that the chemot actic signal induced by PDGF is dominated by PDGF beta-receptors and s witches from positive at low concentrations to negative at higher conc entrations. Stimulation of DNA synthesis by the three isoforms (as mea sured by [H-3] thymidine incorporation) yielded saturable responses fo r the AB and BB isoforms, with similar efficacy and weak or no respons e for the AA isoform. Concentration-dependent patterns of tyrosine pho sphorylation of certain proteins mirrored the form of,the chemotactic response and suggest one possible underlying regulatory mechanism to a ccount for the disparity between PDGF-induced chemotaxis and DNA synth esis.