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 patency than saphenous vein (SV) grafts. Intimal hyperplasia of SV grafts 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 grafts.


RESULTS
SMCs were isolated from IMA and SV by explant culture and stimulated with serum or platelet-derived growth factor-BB (PDGF-BB). Cell growth was analyzed by explant outgrowth rate, 3H-thymidine incorporation, or cell counting. PDGF receptor expression and autophosphorylation, regulation of mitogen-activated protein kinases (MAPKs), and cyclin-dependent kinase inhibitors (p27Kip1 and p21Cip1) were analyzed by molecular techniques. SMC outgrowth from explants by 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%) increased cell number more rapidly in SV (2 x 10(4)/well to 18+/-4 x 10(4)/well; P<.05) than in IMA (2 x 10(4)/well to 9+/-4 x 10(4)/well; P<.05) over an 8-day period. PDGF-BB (0.01 to 10 ng/mL) stimulated 3H-thymidine incorporation (1347+/-470% above control levels) and increased cell number in SV (2 x 10(4)/well to 5+/-1 x 10(4)/well; P<.05) but not in IMA. PDGF alpha- and beta-receptors were similarly expressed and were activated in both SV and IMA. PDGF-BB induced a similar MAPK activation (kinetics and maximal activity) in both SV and IMA cells but increased MAPK protein level only in SV. Furthermore, PDGF-BB markedly downregulated the cell cycle inhibitor p27Kip1 in SV, but this was much less pronounced in IMA.


CONCLUSIONS
SMCs from SVs exhibit enhanced proliferation compared 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 (p27Kip1) 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 versus venous grafts.
Yang
Z
Z
Cardiovascular Research, Institute for Physiology, University Zürich-Irchel, Switzerland.
Oemar
B S
BS
Carrel
T
T
Kipfer
B
B
Julmy
F
F
Lüscher
T F
TF
D015152:Blotting, Northern; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002455:Cell Division; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008297:Male; D008323:Mammary Arteries / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology*; D011233:Precipitin Tests; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D012501:Saphenous Vein / Q000166:cytology / Q000378:metabolism / Q000502:physiology*
D017479:Receptors, Platelet-Derived Growth Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018844:Cyclin-Dependent Kinases