Endothelial Dysfunction, Hemodynamic Forces, and Atherosclerosis

Vascular Endothelium: A Dynamic Interface A central premise of modern vascular biology is that the endothelial lining of the cardiovascular system is a dynami-cally mutable interface, which is locally responsive to various stimuli originating from the circulating blood or neighboring cells and tissues, and thus, can actively participate in the physiological adaptation or pathophysiological dysfunction of a given region of the vasculature.1 From a teleological point of view, the endothelium is well-suited to function in this capac-ity, given its unique anatomical position between blood and tissues and its ability to generate an impressive repertoire of biological effectors (e.g., nitric oxide, eicosanoids, cytokines, growth factors and inhibitors, vasoactive substances, procoagulants and anticoagulants, and fibrinolytic factors and inhibitors). Early studies of the mechanisms underlying this plasticity suggested that many of these endothelial-derived substances, in fact, function as agonist/antagonist pairs in multifactorial pathophysiological balances that serve to regulate hemostasis and thrombosis, inflammation, and other responses to injurious stimuli by the vascular lining. These studies also identified certain humoral substances, such as proinflammatory cytokines (e.g., interleukin-1, tumor necrosis factor, and gamma- interferon) and bacterial products (e.g., Gram negative endotoxins), as potent stimuli that could modify the “set-point” of these various pathophysiological balances. The reproducibility of this humoral mode of stimulation and its wide-reaching biological implications, has led to its extensive study, in both in vitro and in vivo experimental models, as a biochemical paradigm of endothelial activation.2,3 In addition to these humoral stimuli, both systemic and local, the vascular endothelium is also constantly exposed to a spectrum of hemodynamic forces generated by pulsatile blood flow. These forces include hydrostatic pressures, cyclic strains, and wall shear stresses. There is increasing evidence that these biomechanical stimuli can directly influence endothelial structure and function, acutely and chronically, thus constituting a novel paradigm of endothelial activation. This brief editorial review is intended to provide a perspective on the role of biomechanical forces, alone and in conjunction with humoral stimuli, as relevant factors in the pathogenesis of atherosclerosis and its complications. This is a rapidly developing field, and the following discussion, therefore, is intended to simply provide a conceptual framework.