Abstract-Mechanical forces are important modulators of cellular function in many tissues and are particularly important in the cardiovascular system. The endothelium, by virtue of its unique location in the vessel wall, responds rapidly and sensitively to the mechanical conditions created by blood flow and the cardiac cycle. In this study, we examine data which suggest that steady laminar shear stress stimulates cellular responses that are essential for endothelial cell function and are atheroprotective. We explore the ability of shear stress to modulate atherogenesis via its effects on endothelial-mediated alterations in coagulation, leukocyte and monocyte migration, smooth muscle growth, lipoprotein uptake and metabolism, and endothelial cell survival. We also propose a model of signal transduction for the endothelial cell response to shear stress including possible mechanotransducers (integrins, caveolae, ion channels, and G proteins N umerous studies suggest that normal functioning of the endothelium is critical in limiting the development of atherosclerosis, as illustrated by the correlation between risk factors for atherosclerosis (smoking, high cholesterol, high homocysteine, decreased estrogen, increasing age, and hypertension) and endothelial dysfunction.1 Endothelial cells play a critical role in vascular homeostasis by performing many functions. They sense and integrate hemodynamic and hormonal stimuli and effect alterations in vascular function through the secretion of various mediator proteins and molecules.2 As a result of these properties, endothelial cells modulate biological processes related to the blood vessel wall, including regulation of the permeability of plasma lipoproteins, adhesion of leukocytes, and release of prothrombotic and antithrombotic factors, growth factors, and vasoactive substances.3 Impairment of these endothelial cell-mediated processes has been postulated to play a central role in the pathogenesis of atherosclerosis. 1Just as other tissues have developed mechanisms to detect changes in the physiological conditions to which they are exposed, endothelial cells respond not only to humoral factors in the circulation but also to the mechanical conditions created by blood flow and the cardiac cycle. 4 As a result of their unique location, endothelial cells experience three primary mechanical forces: pressure, created by the hydrostatic forces of blood within the blood vessel; circumferential stretch or tension, created as a result of defined intercellular connections between the endothelial cells that exert longitudinal forces on the cell during vasomotion; and shear stress, the dragging frictional force created by blood flow. Of these forces, shear stress appears to be a particularly important hemodynamic force because it stimulates the release of vasoactive substances and changes gene expression, cell metabolism, and cell morphology. 4 The nature and magnitude of shear stress plays an important role in long-term maintenance of the structure and function of the blood vessel. T...

Fluid shear stress is one of the most important mechanical forces acting upon vascular endothelium, because of its location at the interface between the bloodstream and vascular wall. Recent evidence indicates that several intracellular signaling events are stimulated in endothelial cells in response to shear stress. Through these events, shear stress modulates endothelial cell function and vascular structure, but the molecular basis of shear stress mechanotransduction remains to be elucidated. In our research we have focused on three temporal signal responses to shear stress: (1) production of nitric oxide (NO) as an immediate response; (2) activation of extracellular-regulated kinases (ERK1/2; p44/p42 mitogen-activated protein (MAP) kinases) as a rapid response, and (3) tyrosine phosphorylation of focal adhesion kinase (FAK) as a sustained response. In terms of vessel biology, NO production, and ERK1/2 and FAK activation seem to be correlated with vascular homeostasis, gene expression and cytoskeletal rearrangement, respectively. In this review, we discuss the mechanisms that establish the temporal order of shear stress-stimulated responses based on a hierarchy for assembly of signal transduction molecules at the cell plasma membrane.

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Mechano-sensitive regulation of endothelial cells (EC)function by shear stress is critical for flow-induced vasodilation and gene expression. Previous studies by our laboratory demonstrated that shear stress activates the 44-and 42-kDa extracellular signal-regulated kinases (ERK1/2) in EC in a time-and force-dependent manner. ERK1/2 activation was inhibited by protein kinase C (PKC) down-regulation with phorbol 12,13-dibutyrate (1 M for 24 h) but not by calcium chelation with BAPTA-AM (acetoxymethyl ester of BAPTA) (75 M for 30 min), suggesting that a novel PKC isoform (␦, ⑀, , ) mediates shear stress-induced ERK1/2 activation. Western blotting with PKC isoform-specific antibodies demonstrated expression of PKC-␣, -⑀, and -isoforms in EC. PKC-⑀ was specifically inhibited by transfection with antisense PKC-⑀ phosphorothioate oligonucleotides (1,000 nM for 6 h). Antisense treatment decreased PKC-⑀ protein levels by 80 ؎ 13% after 72 h and completely inhibited shear stress-stimulated ERK1/2 activation. Scrambled PKC-⑀ oligonucleotides and antisense PKC-␣ and PKC-oligonucleotides had no effect on ERK1/2 activity. PKC-⑀ appeared specific for mechano-sensitive ERK1/2 activation, as antisense PKC-⑀ oligonucleotides did not inhibit ERK1/2 activation by EGF or bradykinin but did inhibit ERK1/2 activation upon EC adhesion to fibronectin. These results define a pathway for shear stress-mediated ERK1/2 activation and establish a new function for PKC-⑀ as part of a mechano-sensitive signal transduction pathway in EC.

Hemostatic mechanisms are an integral part of the human physiology. Traditionally divided into intrinsic and extrinsic arms, the coagulation cascade converges, through the interactions of many different factors, at a common element-thrombin. As a consequence, a number of different agents have been developed to supplement this common, critical step to aid surgical hemostasis. Intraoperative interventions most commonly include sutures and heat-generating cautery devices; however, these methods are sometimes insufficient or inappropriate for a specific procedure or anatomic location, leading to the development of other adjunctive therapies, including topical hemostats. Topical hemostatic agents generally act as active, passive, and combinations therapies, depending on their individual composition and mode of action. We provide a brief review of the normal coagulation cascade, including critical points, followed by a discussion of surgical strategies and adjuctive therapies used to achieve surgical hemostasis and concluding with a discussion of topical thrombins.