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Different Effects of High and Low Shear Stress on Platelet-Derived Growth Factor Isoform Release by Endothelial Cells: Consequences for Smooth Muscle Cell Migration

In the present study, we analyzed the effect of conditioned media (CM) from bovine aortic endothelial cells exposed to laminar shear stress (SS) of 5 dyne/cm2 (SS5) or 15 dyne/cm2 (SS15) for 16 hours on smooth muscle cell (SMC) migration. In response to CM from bovine aortic endothelial cells exposed to SS5 (CMSS5) and SS15 (CMSS15), migration was 45±5.5 and 30±1.5 cells per field, respectively (P <0.05). Similar results were obtained with SS of 2 versus 20 dyne/cm2 and also when SS of 5 and 15 dyne/cm2 lasted 24 hours. Platelet-derived growth factor (PDGF)-AA levels in CMSS5 and CMSS15 were 9±7 and 18±5 ng/106 cells for 16 hours, respectively (P <0.05); PDGF-BB levels in CMSS5 and CMSS15 were 38±10 and 53±10 ng/106 cells for 16 hours, respectively (P <0.05). PDGF receptor &agr; (PDGFR&agr;) and PDGF receptor &bgr; (PDGFR&bgr;) in SMCs were phosphorylated by CMSS15>CMSS5. In response to CMSS15, a neutralizing antibody against PDGF-AA enhanced SMC migration to a level comparable to that of CMSS5; in contrast, antibodies against PDGF-BB abolished SMC migration. Transfection of SMCs with a dominant-negative PDGFR&agr; or PDGFR&bgr; increased or inhibited, respectively, SMC migration in response to CMSS15. Overexpression of wild-type PDGFR&agr; inhibited SMC migration in response to CMSS5, CMSS15, or recombinant PDGF-BB (P <0.001). These results suggest that the ability of high SS to inhibit arterial wall thickening in vivo may be related to enhanced activation of PDGFR&agr; in SMCs by PDGF isoforms secreted by the endothelium.