Effect of fluid shear stress on the growth and metabolism of human aortic smooth muscle cells
Doctor of Philosophy
Upon disruption of the integrity of the endothelial monolayer, smooth muscle cells (SMC) may be directly exposed to blood flow and their behavior may be modulated by the local hemodynamic environment. Furthermore, modeling studies indicate that in the normal vasculature, underlying SMC are exposed to significant shear stresses due to transmural interstitial flaw. To study the contribution of fluid shear stress to SMC growth and metabolism, cultured human aortic smooth muscle cells (hASMC) were subjected to physiological levels of shear stress using parallel plate flow chambers connected to recirculating flow loops. Fluid shear stress decreased the growth rate of hASMC. The cell number at high shear stress levels was significantly lower compared to low levels of shear stress and this was not a result of cell injury. These findings are consistent with in vivo observations in which it was found that areas of low shear stress were associated with greater intimal hyperplasia. Exposure of SMC to shear stress resulted in a rapid nitric oxide (NO) release which was followed by a sustained nitrite production, independent of the level of shear stress in the range of 5-25 dyn/cm$\sp2$. NO production was calcium dependent and was due to activation of a constitutive nitric oxide synthase (NOS) I. The constitutive expression of NOS in SMC and its concomitant activation by shear stress may play a regulatory role in the blood vessel wall in the absence of endothelium following vascular injury, and may also be important in normal vessel homeostasis. Shear stress differentially mediated the expression of thrombin receptor (TR) and tissue plasminogen activator (tPA) in hASMC. The upregulation of tPA and downregulation of TR mRNA and protein by high shear stress are consistent with the relative paucity of lesions in areas of high shear stress within the vasculature, while the downregulation of tPA and upregulation of TR mRNA by low shear stresses are consistent with the known predilection of low shear stress areas to thrombus formation and to vascular cell proliferation. The finding of a domain within the TR promoter that contains a potential shear responsive element offers new insights into these regulatory events.
Physiology; Biomedical engineering; Chemical engineering