ABSTRACT
From the moment the heart starts beating and blood flow is first established for first time in the developing vertebrate embryo, the cardiovascular system is constantly exposed to fluid mechanical forces. The pulsatile nature of blood flow generates a complex interplay of three distinct types of fluid mechanical forces: wall shear stresses, cyclic strains, and hydrostatic pressures (1). These hemodynamic factors act on the cells that comprise the vascular wall, in particular the endothelium, influencing their structure and function (2). There is increasing evidence that mechanical stimulation plays an important role in the development of the vasculature, the maintenance of vascular integrity and homeostasis, and the development of vascular diseases (2-5). The endothelial lining of the heart and vasculature comprise a dynamic interface with the blood and acts as an integrator and transducer of both humoral and mechanical stimuli (3). This single-cell-thick layer is able to rapidly sense changes in blood flow and respond by secreting or metabolizing potent vasoactive substances (e.g., nitric oxide) that contribute to pressure/flow homeostasis. In face of chronic flow changes, a more deliberate structural remodeling of the vessel wall also can occur via endothelium-dependent mechanisms (6,7). These adaptive responses reflect rapid changes in protein function, enzymatic activity, and transient or long-lasting effects on endothelial gene expression. Moreover, multiple studies in in vitro model systems have confirmed that fluid shear stresses, comparable to those generated by the frictional force of blood flow on the endothelial lining in vivo, can directly influence protein function, enzymatic activities (1), and transcriptional events in cultured endothelial monolayers influencing their functional phenotype (8-11). It remains a central question in the field of vascular biology how these mechanical forces are sensed by the cells of the blood vessel wall and then translated into pathophysiologically relevant phenotypic changes. Activation of various signaling cascades and transcription
factor systems have helped to provide insight into the cellular mechanisms linking shear stress stimuli and genetic regulatory events. It is now clear that endothelial cells have the capacity not only to sense fluid mechanical forces, but also to discriminate among distinct types of forces (8,10) Collectively, these observations strongly suggest that fluid mechanical forces can act as local “extrinsic modifiers” of endothelial functions within the vascular tree. This chapter focuses on the emerging areas where the role of fluid mechanical forces, in particular shear stress, is being explored with exquisite experimental approaches that allow us to unveil the molecular links between mechanics and biology.
