PDGF-induced proliferation in human arterial and venous smooth muscle cells: molecular basis for differential effects of PDGF isoforms.

The proliferative phenotype of artery and veins is different from each other and appears to have clinically significant consequences. Coronary artery bypass grafting with the autologous saphenous vein or internal mammary artery is widely used to treat atherosclerotic coronary artery disease. Graft failure due to stenosis occurs much more frequently in saphenous vein grafts than internal mammary artery grafts [Loop et al., 1986; Motwani and Topol, 1998]. Graft stenosis is most frequently caused by neointimal hyperplasia, another type of vascular proliferative disease. Similarly, most neointimal hyperplasia occurs at the graft-venous anastomosis of hemodialysis arteriovenous grafts, resulting in 60% graft loss in the first year [US Renal Data System, 2007]. In contrast, atherosclerosis occurs in arteries but rarely in veins despite the exposure of both arteries and veins to the same systemic risk factors such as smoking and dyslipidemia. While hemodynamic and other local factors probably play a role in the different susceptibilities to atherosclerosis and neointimal hyperplasia between artery and veins, it is likely that the observed dissimilarities can be at least partially explained by intrinsic phenotypic differences between arterial and venous smooth muscle cells (SMCs). These phenotypic differences would include the activation of different mitogenic signaling pathways. Platelet-derived growth factor (PDGF) is the most potent SMC mitogen released at the site of injury by platelets, endothelial cells, SMCs, and many other cell types [Heldin and Westermark, 1999; Raines, 2004]. The role for PDGF in the pathogenesis of arterial injury disorders, including atherosclerosis and post-angioplasty restenosis, has been well established. However, the effects of various PDGF isoforms and the differences between arterial and venous SMCs in their responses to these isoforms are largely unknown and may explain the clinically observed differences between the arterial and venous diseases. PDGF is a dimer composed of disulfide-linked polypeptides termed A-chain and B-chain. At least three isoforms (PDGF-AA, PDGF-AB, and PDGF-BB) are present in human platelets in comparable quantities [Hart et al., 1990]. The PDGF-C and PDGF-D chains were discovered more recently and their biology is not well established [Li et al., 2000; Bergsten et al., 2001; LaRochelle et al., 2001]. The role and expression of PDGF-C and PDGF-D in arteries and in atherosclerotic lesions remain unclear. Recently, Karvinen et al. [2009] reported that PDGF-C was strongly expressed in endothelial cells in both normal arteries and atherosclerotic lesions whereas PDGF-D was only weakly expressed in these cells. The functions of PDGF-CC and PDGF-DD have been explored and reviewed [Reigstad et al., 2005; Wagsater et al., 2009] and will not be further discussed in this paper. PDGF stimulates cell proliferation by binding to PDGF receptor α (PDGF-Rα) or PDGF receptor β (PDGF-Rβ), causing receptor dimerization and autophosphorylation. Previous studies have demonstrated that PDGF-AA activates only αα receptor dimers, PDGF-AB activates both αα and αβ receptor dimers, whereas PDGF-BB activates αα, αβ, and ββ receptor dimers [Heldin et al., 1998]. Many studies have demonstrated the pathogenic roles of PDGF-AB, PDGF-BB, and PDGF-Rβ in the formation of atherosclerotic and neointimal hyperplasia lesions. However, their roles in the pathogenesis of venous diseases and the roles of PDGF-AA and PDGF-Rα in vascular disorders are largely unknown. We have previously reported that the proliferation of human venous SMCs was more responsive to PDGF-AB stimulation compared to arterial SMCs [Li et al., 2006a]. In the present study, we investigated the proliferative effects of PDGF-BB and PDGF-AA on arterial and venous SMCs and identified differences in the underlying signaling pathways that led to different responses to these PDGF isoforms between arterial and venous SMCs. These results provide unique insights into the molecular basis of the varying susceptibility to proliferative disorders between arteries and veins.