The focal nature of the atherosclerotic lesions in the arterial trees demonstrates the importance of hemodynamics; namely, shear stress, in regulating the biological activities of endothelial cells (EC). In vivo, velocity profiles are asymmetric in shape due to vessel geometry, as well as the time- and spatial-varying components of pulsatile flow. The emerging Micro Electro Mechanical Systems (MEMS) technology offers a new entry point to overcome the existing difficulties. Atherosclerosis is considered to be an inflammatory disease. We hypothesize that disturbed flow with fluctuating parameters such as frequency, direction, and amplitudes plays a distinct role in modulating the inflammatory responses in the arterial bifurcations. In contrast, unidirectional pulsatile flow, and the upstroke slopes or defined as slew rates, downregulate the inflammatory responses. To test our hypotheses, three specific aims are proposed.
Specific Aim 1 : To acquire real-time unsteady shear stress known to occur in the arterial bifurcations. Newly designed channel will be used to generate steady, pulsatile, or oscillatory flow to cultured ECs. We will develop and fabricate MEMS shear stress sensors to provide both the spatial and temporal resolution necessary to link shear stress with the inflammatory responses of cultured ECs.
Specific Aim 2 : To elucidate the molecular and, consequently, functional responses of ECs to pulsatile vs. oscillatory shear stress. In vitro, we will simulate EC and monocyte interactions in the lateral wall of arterial bifurcations where disturbed flow occurs. In parallel, we will investigate the dynamic relation between the inflammatory mediators such as monocyte chemoattractant protein-1 (MCP-1) and vasodilators such as nitric oxide (NO).
Specific Aim 3 : To demonstrate the significance of high vs. low shear stress slew rates known to occur during physical activities on ECs pretreated with oxidized lipid. We will isolate the effects of slew rates on ECs by investigating EC morphologic changes, interactions with monocytes, and inflammatory mediators. This proposed project is both design-directed and hypothesis-driven. By combining MEMS technology and vascular biology, this proposal will generate new insights into the mechanism of flow regulation at the arterial bifurcations.
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