DIFFERENT PROLIFERATIVE PROPERTIES OF SMOOTH-MUSCLE CELLS OF HUMAN ARTERIAL AND VENOUS BYPASS VESSELS - ROLE OF PDGF RECEPTORS, MITOGEN-ACTIVATED PROTEIN-KINASE, AND CYCLIN-DEPENDENT KINASE INHIBITORS

Background-Internal mammary artery (IMA) bypass grafts have a higher p atency than saphenous vein (SV) grafts. Intimal hyperplasia of SV graf ts is due to smooth muscle cell (SMC) proliferation and migration. We hypothesized that different SMC growth activity exists in IMA and SV, which may explain the different patencies of arterial and venous graft s. Methods and Results-SMCs were isolated from IMA and SV by explant c ulture and stimulated with serum or platelet-derived growth factor-BB (PDGF-BB). Cell growth was analyzed by explant outgrowth rate, H-3-thy midine incorporation, or cell counting. PDGF receptor expression and a utophosphorylation, regulation of mitogen-activated protein kinases (M APKs), and cyclin-dependent kinase inhibitors (p27(Kip1) and p21(Cip1) ) were analyzed by molecular techniques. SMC outgrowth from explants b y serum (20%) over a 20-day period was more pronounced in SV (37+/-5%) than in IMA (4+/-3%; P<.001) of the same patients. Serum (10%) increa sed cell number more rapidly in SV (2X10(4)/well to 18+/-4X10(4)/well; P<.05) than in IMA (2X10(4)/well to 9+/-4X10(4)/well; P<.05) over an 8-day period. PDGF-BB (0.01 to 10 ng/mL) stimulated H-3-thymidine inco rporation (1347+/-470% above control levels) and increased cell number in SV (2X10(4)/well to 5X10(4)/well: P<.05) but not in IMA. PDGF alph a- and beta-receptors were similarly expressed and were activated in b oth SV and IMA. PDGF-BB induced a similar MAPK activation (kinetics an d maximal activity) in both SV and IMA cells but increased MAPK protei n level only in SV. Furthermore, PDGF-BB markedly downregulated the ce ll cycle inhibitor p27(Kip1)) in SV, but this was much less pronounced in IMA. Conclusions-SMCs from SVs exhibit enhanced proliferation comp ared with IMA in spite of functional growth factor receptor expression and MAPK activation. However, PDGF increased MAPK protein level only in SV and downregulated cell cycle inhibitor (p27(Kip1)) more potently in SV than in IMA. This may explain the resistance to growth stimuli of IMA SMCs and may contribute to the longer patency of arterial versu s venous grafts.