Molecular and mechanical bases of focal lipid accumulation in arterial wall

Abstract

Mechanical forces such as shear stress can modulate gene and protein expressions and hence cellular functions by activating membrane sensors and intracellular signaling. Using cultured endothelial cells, we have shown that laminar shear stress causes a transient increase in monocyte chemotactic protein-1 (MCP-1) expression, which involves the Ras-MAP kinase signaling pathway. We have demonstrated that integrins and the vascular endothelial growth factor receptor Flk-1 can sense shear stress, with integrins being upstream to Flk-1. Other possible membrane components involved in the sensing of shear stress include G-protein coupled receptors, intercellular junction proteins, membrane glycocalyx, and the lipid bilayer. Mechano-transduction involves the participation of a multitude of sensors, signaling molecules, and genes. Microarray analysis has demonstrated that shear stress can upregulate and downregulate different genes. Sustained shear stress downregulates atherogenic genes (e.g., MCP-1 and the genes that facilitate lipid accumulation) and upregulates growth-arrest genes. In contrast, disturbed flow observed at branch points and simulated in step-flow channels causes sustained activation of MCP-1 and the genes facilitating cell turnover and lipid accumulation. These findings provide a molecular basis for the explanation of the preferential localization of atherosclerotic lesions at regions of disturbed flow, such as the arterial branch points. The combination of mechanics and biology (from molecules-cells to organs-systems) can help to elucidate the physiological processes of mechano-chemical transduction and improving the methods of the management of important clinical conditions such as coronary artery disease.