Molecular basis of rheological modulation of endothelial functions: importance of stress direction

Vascular endothelial cells (EC) play significant roles in regulating circulatory functions. Shear stress and stretch can modulate EC functions by activating mechano-sensors, signaling pathways, and gene and protein expressions. Laminar shear stress with a significant forward direction causes transient activations of monocyte chemotactic protein-1 (MCP-1), sterol response element binding protein (SREBP), and proliferative genes. Sustained laminar shear stress down-regulates these genes and up-regulates genes that inhibit EC growth. In EC subjected to complex flow patterns with little forward direction, activations of MCP-1, SREBP, and proliferation genes become sustained, and mitosis and apoptosis are enhanced. Cyclic uniaxial stretch causes actin stress fibers to orient perpendicular to stretch direction, with a consequent reduction of intracellular stress, transient JNK activation, and protection of EC against apoptosis. Cyclic biaxial stretch without a preferred direction has opposite effects. In the straight part of arterial tree, laminar shear stress with a net forward direction and uniaxial strain in the circumferential direction have anti-atherogenic effects. At vascular branch points, the complex shear flow and mechanical strain with little net direction are atherogenic. Therefore, the direction of stress has important influences on the biorheological effects of flow and deformation on vascular endothelium in health and disease.