Shear stress distribution on beam cross-sections under shear loading

In this work, some results obtained by Trabucho and Viaño for the shear stress distribution in beam cross sections using asymptotic expansions of the three-dimensional elasticity equations are compared with those calculated by the classical formulae of the Strength of Materials. We use beams with rectangular and circular cross section to compare the degree of accuracy reached by each method.

Fluid shear stress inhibits TNF-α activation of JNK but not ERK1/2 or p38 in human umbilical vein endothelial cells: Inhibitory crosstalk among MAPK family members

Atherosclerosis preferentially occurs in areas of turbulent flow and low fluid shear stress, whereas laminar flow and high shear stress are atheroprotective. Inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and IL-1 stimulate expression of endothelial cell (EC) genes that may promote atherosclerosis. TNF-α and IL-1 regulate gene expression in ECs, in part, by stimulating mitogen-activated protein kinases (MAPK), which phosphorylate transcription factors. We hypothesized that steady laminar flow inhibits cytokine-mediated activation of MAPK in EC. To test this hypothesis, we determined the effects of flow (shear stress = 12 dynes/cm2) on TNF-α and IL-1-stimulated activity of three MAPK in human umbilical vein ECs (HUVEC): extracellular signal-regulated kinase (ERK1/2), p38, and c-Jun N-terminal kinase (JNK). Flow alone stimulated ERK1/2 and p38 activity but decreased JNK activity compared with static controls. TNF-α or IL-1 alone activated ERK1/2, p38, and JNK maximally at 15 min in HUVEC. Preexposing HUVEC for 10 min to flow inhibited TNF-α and IL-1 activation of JNK by 46% and 49%, respectively, but had no significant effect on ERK1/2 or p38 activation. Incubation of HUVEC with PD98059, which inhibits flow-mediated ERK1/2 activation, prevented flow from inhibiting cytokine activation of JNK. Phorbol 12-myristate 13-acetate, which strongly activates ERK1/2, also inhibited TNF-α activation of JNK. These findings indicate that fluid shear stress inhibits TNF-α-mediated signaling events in HUVEC via the activation of the ERK1/2 signaling pathway. Inhibition of TNF-α signal transduction represents a mechanism by which steady laminar flow may exert atheroprotective effects on the endothelium.

Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress.

Early atherosclerotic lesions develop in a topographical pattern that strongly suggests involvement of hemodynamic forces in their pathogenesis. We hypothesized that certain endothelial genes, which exhibit differential responsiveness to distinct fluid mechanical stimuli, may participate in the atherogenic process by modulating, on a local level within the arterial wall, the effects of systemic risk factors. A differential display strategy using cultured human endothelial cells has identified two genes, manganese superoxide dismutase and cyclooxygenase-2, that exhibit selective and sustained up-regulation by steady laminar shear stress (LSS). Turbulent shear stress, a nonlaminar fluid mechanical stimulus, does not induce these genes. The endothelial form of nitric oxide synthase also demonstrates a similar LSS-selective pattern of induction. Thus, three genes with potential atheroprotective (antioxidant, antithrombotic, and antiadhesive) activities manifest a differential response to distinct fluid mechanical stimuli, providing a possible mechanistic link between endothelial gene expression and early events in atherogenesis. The activities of these and other LSS-responsive genes may have important implications for the pathogenesis and prevention of atherosclerosis.

The cis-acting phorbol ester "12-O-tetradecanoylphorbol 13-acetate"-responsive element is involved in shear stress-induced monocyte chemotactic protein 1 gene expression.

Vascular endothelial cells, serving as a barrier between vessel and blood, are exposed to shear stress in the body. Although endothelial responses to shear stress are important in physiological adaption to the hemodynamic environments, they can also contribute to pathological conditions--e.g., in atherosclerosis and reperfusion injury. We have previously shown that shear stress mediates a biphasic response of monocyte chemotactic protein 1 (MCP-1) gene expression in vascular endothelial cells and that the regulation is at the transcriptional level. These observations led us to functionally analyze the 550-bp promoter region of the MCP-1-encoding gene to define the cis element responding to shear stress. The shear stress/luciferase assay on the deletion constructs revealed that a 38-bp segment (-53 to -90 bp relative to the transcription initiation site) containing two divergent phorbol ester "12-O-tetradecanoylphorbol 13-acetate" (TPA)-responsive elements (TRE) is critical for shear inducibility. Site-specific mutations on these two sites further demonstrated that the proximal one (TGACTCC) but not the distal one (TCACTCA) was shear-responsive. Shear inducibility was lost after the mutation or deletion of the proximal site. This molecular mechanism of shear inducibility of the MCP-1 gene was functional in both the epithelial-like HeLa cells and bovine aortic endothelial cells (BAEC). In a construct with four copies of the TRE consensus sequences TGACTACA followed by the rat prolactin minimal promoter and luciferase gene, shear stress induced the reporter activities by 35-fold and 7-fold in HeLa cells and BAEC, respectively. The application of shear stress on BAEC also induced a rapid and transient phosphorylation of mitogen-activated protein kinases. Pretreatment of BAEC with TPA attenuated the shear-induced mitogen-activated protein kinase phosphorylation, suggesting that shear stress and TPA share a similar signal transduction pathway in activating cells. The present study provides a molecular basis for the transient induction of MCP-1 gene by shear stress.

Investigating the Role of cAMP-Signaling in the Regulation of Vascular Endothelial Cell Adaptive Responses to Fluid Shear Stress

The circulating blood exerts a force on the vascular endothelium, termed fluid shear stress (FSS), which directly impacts numerous vascular endothelial cell (VEC) functions. For example, high rates of linear and undisturbed (i.e. laminar) blood flow maintains a protective and quiescent VEC phenotype. Meanwhile, deviations in blood flow, which can occur at vascular branchpoints and large curvatures, create areas of low, and/or oscillatory FSS, and promote a pro-inflammatory, pro-thrombotic and hyperpermeable phenotype. Indeed, it is known that these areas are prone to the development of atherosclerotic lesions. Herein, we show that cyclic nucleotide phosphodiesterase (PDE) 4D (PDE4D) activity is increased by FSS in human arterial endothelial cells (HAECs) and that this activation regulates the activity of cAMP-effector protein, Exchange Protein-activated by cAMP-1 (EPAC1), in these cells. Importantly, we also show that these events directly and critically impact HAEC responses to FSS, especially when FSS levels are low. Both morphological events induced by FSS, as measured by changes in cell alignment and elongation in the direction of FSS, and the expression of critical FSS-regulated genes, including Krüppel-like factor 2 (KLF2), endothelial nitric oxide synthase (eNOS) and thrombomodlin (TM), are mediated by EPAC1/PDE4D signaling. At a mechanistic level, we show that EPAC1/PDE4D acts through the vascular endothelial-cadherin (VECAD)/ platelet-cell adhesion molecule-1 (PECAM1)/vascular endothelial growth factor receptor 2 (VEGFR2) mechanosensor to activate downstream signaling though Akt. Given the critical role of PDE4D in mediating these effects, we also investigated the impact of various patterns of FSS on the expression of individual PDE genes in HAECs. Notably, PDE2A was significantly upregulated in response to high, laminar FSS, while PDE3A was upregulated under low, oscillatory FSS conditions only. These data may provide novel therapeutic targets to limit FSS-dependent endothelial cell dysfunction (ECD) and atherosclerotic development.

Measurement of water surface roughness and wind shear stress by the use of a pitot tube in a laboratory wave channel /

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