© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Heterogeneity in the response of vascular smooth muscle to heparin: altered signaling in heparin-resistant cells
Department of Laboratory Medicine and Pathobiology, University of Toronto, 100 College St., Toronto, Canada M5G 1L5
* Corresponding author. Tel.: +1-416-978-3972; fax: +1-416-978-5650 doug.templeton{at}utoronto.ca
Objective: Vascular smooth muscle cells show phenotypic heterogeneity in vivo that affects the extent to which they respond to the antimitogenic effects of heparin. In vitro, heparin-resistant cells are readily selected. This study was undertaken to determine whether differences in the antiproliferative response to heparin involve differences in activity of heparin-sensitive signal transduction pathways. Methods: Rat thoracic aorta smooth muscle cells (ASMC) at early passage together with two established vascular smooth muscle lines, PAC-1 and A10, were examined before and after selection for growth in the presence of heparin (10 µg/ml). Cells were rendered quiescent and then stimulated with serum. Results: The three cell types showed different sensitivities to the antimitogenic effects of heparin. With respect to [3H]thymidine incorporation, A10 cells were insensitive to 1 µg/ml heparin whereas PAC-1 cells responded down to 0.05 µg/ml and ASMC were of intermediate sensitivity. ASMC and PAC-1 cells but not A10 showed a decrease in c-fos mRNA in response to 1 µg/ml heparin, and a decrease in the c-Fos content of AP-1 DNA binding activity. None of the cells had decreased c-jun mRNA in the presence of heparin. Although induction of c-fos by serum is thought to signal through the Erk mitogen activated protein kinase family, Erk activity was decreased more by 1 µg/ml heparin in A10 cells than in PAC-1 or ASMC. When cells were selected by growth in the presence of 10 µg/ml heparin, A10 cells were unaffected but PAC-1 and ASMC showed a blunted effect of heparin on serum stimulation. In contrast to A10 and their controls not exposed to continuous heparin, heparin-selected PAC-1 and ASMC showed a diminished ability to induce c-fos in response to serum. Conclusions: Smooth muscle cell lines show different responses to the antimitogenic effects of heparin that correlate with the heparin sensitivity of c-Fos/c-Jun expression. Although Erk is implicated in c-fos induction, cells comparatively resistant to heparin still show heparin-dependent inhibition of Erk activation, suggesting that other pathways may be more important for heparin resistance. Furthermore, cells selected for heparin resistance may develop c-fos-independent pathways for proliferation.
KEYWORDS ASMC, Aortic smooth muscle cell; FBS, Fetal bovine serum; FGF-2, Basic fibroblast growth factor; MAPK, Mitogen-activated protein kinase; PDGF, Platelet-derived growth factor; PKC, Protein kinase C; VSMC, vascular smooth muscle cell
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