Pattern Formation of Vascular Smooth Muscle Cells Subject to Nonuniform Fluid Shear Stress: Role of Platelet-Derived Growth Factor β-Receptor and Src

Blood vessels are subject to fluid shear stress, a hemodynamic factor that inhibits the mitogenic activities of vascular cells. The presence of nonuniform shear stress has been shown to exert graded suppression of cell proliferation and induces the formation of cell density gradients, which in turn regulates the direction of SMC migration and alignment. Here, we investigate the role of platelet-derived growth factor (PDGF) β-receptor and Src in the regulation of such processes. In experimental models with vascular polymer implants, SMCs migrated from the vessel media into the neointima of the implant under defined fluid shear stress. In a nonuniform shear model, blood shear stress suppressed the expression of PDGF βreceptor and the phosphorylation of Src in a shear level-dependent manner, resulting in the formation of mitogen gradients, which were consistent with the gradient of cell density as well as the alignment of SMCs. In contrast, uniform shear stress in a control model elicited an even influence on the activity of mitogenic molecules without modulating the uniformity of cell density, and did not significantly influence the direction of SMC alignment. The suppression of the PDGF β-receptor tyrosine kinase and Src with pharmacological substances diminished the gradients of mitogens and cell density, and reduced the influence of nonuniform shear stress on SMC alignment. These observations suggest that PDGF β-receptor and Src possibly serve as mediating factors in nonuniform shear-induced formation of cell density gradients and alignment of SMCs in the neointima of vascular polymer implants.