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At least 19 recordsLinked to original sources
PubMed2002

Activation of Rac1 by shear stress in endothelial cells mediates both cytoskeletal reorganization and effects on gene expression.

Hemodynamic shear stress is a fundamental determinant of vascular remodeling and atherogenesis. Changes in focal adhesions, cytoskeletal organization and gene expression are major responses of endothelial cells to shear stress. Here, we show that activation of the small GTPase Rac is essential for gene expression and for providing spatial information for shear stress-induced cell alignment. Fluorescence resonance energy transfer (FRET) localizes activated Rac1 in the direction of flow. This directional Rac1 activation is downstream of shear-induced new integrin binding to extracellular matrix. Additionally, Rac1 mediates flow-induced stimulation of nuclear factor kappaB (NF-kappaB) and the subsequent expression of intercellular cell adhesion molecule 1 (ICAM-1), an adhesion receptor involved in the recruitment of leukocytes to atherosclerotic plaque. These studies provide a unifying model linking three of the main responses to shear stress that mediate both normal adaptation to hemodynamic forces and inflammatory dysfunction of endothelial cells in atherosclerosis.

Animals↗
PubMed2025

High Hcy regulates fluid shear stress pathway activity through histone H3K79 homocysteinylation in hyperhomocysteinemia-related child hypertension.

BACKGROUND: The rise of hypertension in children has been increasingly associated with hyperhomocysteinemia (HHcy), which is recognized as a major risk factor. However, the underlying mechanisms linking homocysteine and hypertension (termed HHYP) are not fully understood. METHODS: This study utilized plasma samples from 27 control children and 27 children with HHYP (aged 8 ~ 16 years) for TMT6-labeled proteomic quantification, identifying significant altered proteins. Bioinformatics analysis revealed pathway alterations. Verification was carried out via parallel reaction monitoring (PRM) and western blot (WB) analyses. Additionally, a rat model of HHYP induced by high methionine diets, and umbilical vein endothelial cell models exposed to high homocysteine (hcy) levels were developed to investigate the molecular underpinnings further. Protein expression changes and epigenetic modifications were assessed using WB, immunohistochemistry (IHC), and ChIP-qPCR techniques. RESULTS: Key findings indicated that 357 proteins and 69 pathways were altered in children with HHYP. Specifically, 12 proteins within the fluid shear stress and atherosclerosis (FSSA) pathway showed differential expression, including the downregulation of TRX1 and GPX1 and the upregulation of ICAM1. The same expression patterns were noted in both the HHYP rat aortic tissues and the high hcy cultured endothelial cells. Moreover, elevated H3K79hcy modification levels were observed alongside epigenetic regulation of genes related to the FSSA pathway. Importantly, folic acid (FA), a medication frequently used in the clinical treatment of HHYP, has been demonstrated to effectively reverse H3K79hcy modifications and restore the disrupted FSSA pathway in both animal models and cell cultures. CONCLUSIONS: The present study suggests that HHcy may contribute to hypertension through the epigenetic dysregulation of the FSSA pathway mediated by H3K79hcy. Furthermore, the pediatric proteomics data gleaned from this study offer new clinical insights into the pathophysiology of HHYP in children.

Hyperhomocysteinemia↗
PubMed1977

Rheology of composite filling material pastes.

The rheology of composite pastes in the unset state has been studied using a cone and plate viscometer. All materials behaved as Bingham bodies, exhibiting linear shear stress-shear rate plots, with a positive shear-stress intercept (the yield stress of the material). The shape of the plot gave the coefficient of viscosity of the material; at sufficiently high shear rates, shear failure occurred, marked by a breakdown of the linear relationship. The materials studied gave a very wide range of the various rheological factors.

Composite Resins↗
PubMed1979

Shear stress-induced changes in platelet reactivity.

We have investigated the effects on platelet function of a physiologic shear stress. The aggregation to thrombin and collagen, the release reaction [(14C) serotonin] and the procoagulant activity of washed platelet suspensions were assayed on samples undergoing laminar oscillatory flow for 20 minutes at 37 degree C in polyethylene tubes, and on paired samples kept at rest. The pulse rate was established at 72 cycles per minute and the shear stress at the wall estimated at 26.2 dynes/cm2. The platelet suspensions were prepared at 37 degree C from blood samples of 15 healthy volunteers and 15 patients with the diagnosis of coronary artery disease proven by angiography. Our results show enhancement of platelet aggregation in samples undergoing oscillatory flow. Furthermore, platelets from coronary patients gained additional procoagulant activity. However, no change was encountered in the rate and speed of the release reaction. It is concluded that exposure to a high shear stress within an oscillatory flow system enhances platelet reactivity; this reaction may take part in the production of platelet and coagulation changes seen in the atherosclerotic patient and after strenuous physical exercise.

Adult↗
PubMed1978

Platelet lysis and aggregation in shear fields.

A rotational viscometer was used to study the effects of shear stress on platelets in human platelet-rich plasma (PRP). For 5-min exposure times, shear stresses above 160 dynes/cm2 induced platelet lysis (as determined by release of platelet lactic dehydrogenase). For 30-s exposure times, shear stresses greater than 600 dynes/cm2 were required to induce platelet lysis. The platelet counts of sheared PRP were decreased to as low as one-fifth the original count due largely to shear-induced aggregation. The count is a minimum at intermediate stress levels (200-400 dynes/cm2). Higher stresses induce disaggregation as well as lysis. The diminution in the counts was partially reversed in 2 h incubation after cessation of shearing. Experiments were carried out with three different viscometer configurations so that the shear stress and the solid surface area access could be varied independently. Surface access was not a significant variable in the conditions of the experiments. Thus aggregation and lysis may be induced by stress effects alone as well as by solid surface effects. The results also show that the response of platelets to shear stress is strongly dependent on exposure time. Platelets are much less resistant to shear stress than red cells for relatively long exposure times. However, the converse is true for very short exposure times.

Blood Platelets↗
PubMed1979

Enzyme release and morphological changes in leukocytes induced by mechanical trauma.

Polymorphonuclear (PMN) leukocytes exposed to mechanical trauma in vitro will release enzymes both from azurophilic and specific granules at shear stress levels of between 75 and 150 dyn/cm2 for 10 min. In addition, at these shear stresses the leukocyte count in whole blood decreased only slightly and the number of ruptured leukocytes on Wright-stained blood films increased significantly. At higher shear stresses, enzyme release and leukocyte damage increased monotonically. Transmission electron microscopy evaluation of sheared PMNs revealed that remaining intact cells had minor morphological changes at stresses of 150 dyn/cm2. They were characterized by clublike cytoplasmic potrusions, spherical shape, and a circumferential distribution of cytoplasmic granules. At higher shear stresses (600 dyn/cm2) cell destruction was marked. Intact PMNs contained fewer cytoplasmic granules, a large number of vacuoles, and condensed nuclear chromatin. These studies show that PMN morphology and function are at least as sensitive to mechanical trauma as similar platelet alterations seen in other studies.

Alkaline Phosphatase↗
PubMedDate not supplied

A quantitative study of the localization of atherosclerotic lesions in the rabbit aorta.

A quantitative study of the size and location of early sudanophilic lesions has been carried out on the aortae of five rabbits. The atherosclerotic lesions were induced by feeding an average of 114 (+/- 3.7) egg yolks over an average period of 83 (+/- 1.7) days. The aortic lesions were visualuized by gross staining with Sudan III and measured by the polar coordinate method. The lesions were almost entirely around orifices: their size was directly proportional to the area of the associated ostium (P less than 0.005). The sudanophilic deposits were located downstream from the ostia in areas believed to experience high shear stresses. The area of the intercostal ostia increased as one proceeded down the thoracic aorta (P less than 0.005). A deviation from the distal distribution pattern was observed where local flow and shear stresses were disturbed. The coronary lesions completely surrounded the ostia, the coeliac lesions had significant proximal components and the left renal and inferior mesenteric lesions were skewed to the right. The study suggests that hemodynamic forces and particularly high shear stress is of considerable importance in both the initiation and localization of early atherosclerotic lesions.

Animals↗
PubMed1977

Macrophage deformability and phagocytosis.

The influence of several metabolic inhibitors and pharmacologic agents on macrophage deformation (induced by fluid shear stress) was examined in relationship to changes in ATP content and phagocytosis of latex beads. Two relatively specific inhibitors of glycolysis (iodoacetate [IA], and sodium fluoride [NaF]) and a sulfhydryl-binding agent (N-ethylmaleimide [NEM] markedly inhibited phagocytosis and reduced cell deformability. A microtubule-disrupting agent (vinblastine) and a highly specific inhibitor of glycolysis (2-deoxyglucose) markedly inhibited phagocytosis without influencing cell deformability. An organomercurial sulfhydryl binding agent p-chloromercuribenzene (PCMBS) and a microfilament-disrupting agent (cytochalasin B) inhibited phagocytosis and increased cell deformability. The effects of these agents on phagocytosis and cell deformability bore no consistent relationship to alterations in cellular content of ATP. The observation that 2-deoxyglucose, the most specific inhibitor of glycolysis examined, reduced ATP content to levels far lower (15 percent of control values) than those achieved by any other agent examined and inhibited phagocytosis without altering cell deformability, suggests that alterations in cell deformability induced by NaF, IA, NEM, PCMBS, and cytochalasin B are not due to inhibition of glycolysis per se, but instead result from direct or indirect effects of these agents on cell constituents, possibly contractile proteins, which are determinants of cell deformability. The finding that cytochalasin B, NEM, PCMBS, and IA interfere with phagocytosis and alter cell deformability, together with evidence that these agents interact with isolated actin and myosin, suggests that contractile proteins are important both in phagocytosis and as determinants of cell deformability. The observation that vinblastine, colchicines, and heavy water (D(2)O) did not alter cell deformability, even though vinblastine caused formation of intracellular crystals of microtubular protein, indicates that microtubules are not major determinants of cell deformability. The observations that beads adhered normally to surfaces of cytochalasin B- and of PCMBS-treated cells and that shear-stress induced deformation was increased whereas phagocytosis was markedly inhibited, suggest that deformation of cells around beads associated with ingestion depends on some form of cellular (contractile?) activity, whereas deformation of cells by fluid shear stress is a passive phenomenon.

4-Chloromercuribenzenesulfonate↗
PubMed2026

A novel G13-RAPGEF2-RAP1 signaling pathway critical for platelet adhesion and aggregation.

Hemostasis and thrombosis are strongly dependent on the unique ability of platelets to rapidly activate integrin receptors and to firmly adhere to sites of injury under shear stress conditions. Central to integrin activation is the small GTPase RAP1, which itself is activated by guanine nucleotide exchange factors (GEFs). CalDAG-GEFI (RASGRP2) is the highest expressed and functionally dominant platelet RAP-GEF. However, a genome-wide association study also suggested a significant role for RAPGEF2 (PDZ-GEFI), a low-expressed RAP-GEF, in human platelet aggregation. Here, we used mice deficient in RAPGEF2 (megakaryocyte-specific, Rapgef2mKO), CalDAG-GEFI (Caldaggef1-/-), or both RAPGEF2 and CalDAG-GEFI (DKO) to characterize the contribution of RAPGEF2 signaling to platelet function, hemostasis, and thrombosis. RAPGEF2 protein was detected in murine and human platelets. Compared with control or Caldaggef1-/- platelets, both RAP1 activation and integrin αIIbβ3-mediated aggregation were significantly diminished in DKO platelets. When compared with controls, Rapgef2mKO platelets exhibited reduced integrin activation, a more reversible aggregation response, and impaired adhesion under conditions of shear stress ex vivo and in vivo. Mechanistic studies strongly suggest that RAPGEF2 operates downstream of receptors coupled to the heterotrimeric G protein G13 (GNA13), such as αIIbβ3 and the thromboxane receptor. Together, our studies provide genetic evidence that RAPGEF2 in platelets operates downstream of G13 as an important regulator of RAP1 signaling and integrin activation, especially under conditions of elevated shear stress. These findings markedly improve our understanding of G protein signaling and integrin function in platelets, with potential implications for the development of improved platelet-targeted therapies for cardiovascular disease.

Animals↗
PubMed2026

Platelet triggering receptor expressed on myeloid cells-like transcript 1 regulation in healthy donors and patients at risk of bleeding and thrombosis.

BACKGROUND: Triggering receptor expressed on myeloid cells-like transcript 1 (TLT-1), a platelet-specific &#x3b1;-granule protein, is implicated in hemostasis, but its regulation remains unclear. Platelet dysfunction contributes to trauma-induced coagulopathy (TIC) and thrombotic complications in trauma or mechanical circulatory support (MCS); however, underlying mechanisms remain poorly understood. OBJECTIVES: This study investigated the molecular mechanisms underlying soluble TLT (sTLT)-1 release and its role as a biomarker of platelet dysfunction in patients with severe trauma or receiving MCS. METHODS: TLT-1 dynamics on platelets exposed to glycoprotein (GP)VI ligand, coagulation, or shear stress in vitro were evaluated by ELISA and immunoblotting. sTLT-1 was measured in plasma from trauma or MCS-treated patients and healthy donors. Associations with TIC, injury severity, and mortality were assessed. RESULTS: Proteolysis of TLT-1 to release a 10- to 17-kDa fragment was metalloproteinase dependent and blocked by ADAM10 and ADAM17 inhibition. Unlike GPVI, platelet TLT-1 exposure increased following PAR-1 activation. sTLT-1 was elevated in trauma patients compared with controls and correlated with TIC (P < .05) and injury severity (P < .01). Receiver-operating characteristic analysis demonstrated discriminatory performance for TIC (area under the curve, 0.78; P = .011), with a Youden cutoff of 1.180 ng/mL yielding 89% sensitivity and 73% specificity. Platelet TLT-1 was basally expressed, mobilized 2.5-fold with activation, and shed in response to GPVI ligation and plasma recalcification. Shear-exposed platelets and plasma from MCS-treated patients exhibited elevated sTLT-1 levels. CONCLUSION: Unlike GPVI, TLT-1 increased on activated platelets and was regulated by ADAM10 and ADAM17. TLT-1 release is triggered by shear stress, GPVI ligands or activated factor X. Plasma sTLT-1 was associated with trauma severity and TIC.

Humans↗
PubMed1979

Transferring load to flesh: part IX. Cushion stiffness effects.

Stresses developed within flesh in contact with a cushion are examined analytically. Compressive, tensile, and shear stresses within flesh in proximity to a bone are given as a function of cushion stiffness (major parameter) and the overall Poisson's ratio of flesh (minor parameter). It is shown that an individual already sitting on a soft cushion receives relatively minor benefit when a still softer cushion is substituted. This result follows from the fairly flat (saturated) trend of both shear and tensile stress with respect to cushion stiffness, once the soft cushion domain (less than 10 PSI) is entered. Only flesh normal stress (compression) responds significantly to incremental changes of stiffness within the soft cushion range; reducing the cushion stiffness 50 percent will typically reduce local compressive stress by roughly 20 percent. While such a gain is real, it is also modest.

Bone and Bones↗
PubMed1979

Biomechanics of the femoral component of total hip prostheses with particular reference to the stress in the bone-cement.

Two-dimensional finite element analyses were used to determine the normal and shear stress distributions at the prostheses-cement and cement-bone interfaces in the femoral component of a total hip replacement. Various combinations of stem, cement and bone stiffnesses were investigated. In particular the influences of stem taper, cement stiffness, prosthesis stiffness and the effect of a plateau, on the cement stresses were examined and compared. It was particulary noticeable that the normal direct stress across the cement in the proximal region of the stem, both literally and medially, as generally compressive. It was found that the more flexible the cement the more uniform were the stress distributions. Furthermore, these stresses increase as the stiffness of the stem decreases.

Biomechanical Phenomena↗
PubMed1979

[Analysis of flexion energy variations of a human red blood cell, of ellipsoid form, in the process of deformation imposed by turbulent tangential flux].

The purpose of the present, morphological analysis is to recognize a functional connection between shear stress tau, which Human Red Cells, treated with glutaraldehyde, are subjected and their energy of bending (U), during the shape transition, turbulent shear-flow dependent, under the hypothesis of "isoareal" transformation. The experimental basis of this analysis is the work of Sutera and Mehrjardi.

Aldehydes↗
PubMed1979

Inhibition of platelet thrombus formation by chlorpromazine acting to diminish haemolysis.

There is increasing evidence that the sudden, unpredicatable event initiating myocardial infarction is fissuring of an atherosclerotic plaque. The resulting haemorrhage into the arterial wall produces obstructive platelet thrombi, just as arterial haemorrhages elsewhere produce haemostatic platelet plugs. It has been suggested that such platelet aggregation depends on ADP originating in red cells which are subjected to excessive haemodynamic stress at the site of haemorrhage. The release of ADP from red cells has been demonstrated in vitro in equivalent condtions of shear stress; and other mechansims, such as activation by collagen, cannot account for the rapidity with which the platelets react. One of us (G.V.R.B.) has suggested that drugs capable of counteracting haemolysis might diminish the activating effect of erythrocytes on platelets and so inhibit their aggregation as thrombi. Thus, chlorpromazine, added to human blood at concentrations which diminish haemoylsis but do not directly affect platelet aggregation, prolonged the 'bleeding time' from small holes in artificial vessels where extravasation is terminated, as in living arterioles, by aggregated platelets. The bleeding time was also prolonged by apyrase, consistent with the conclusion that the chlorpromazine acted through decreasing plasma ADP. We show here that this occurs through the anti-haemolytic action of chlorpromazine.

Adenosine Diphosphate↗
PubMed1979

A functional interpretation of the varanid dentition (Reptilia, Lacertilia, Varanidae).

A cinéradiographic analysis of the feeding movements in Varanus bengalensis produced the following results. The mouth is opened by raising the head (upper jaw) rather than by lowering the lower jaw. Starting from the resting position, the muzzle unit is elevated around 9 degrees relative to the rest of the skull during jaw opening; the quadrate swings anteriorly around 21 degrees. During jaw closure, the snout is depressed around 15 degrees relative to the rest of the skull, hence 6 degrees beyond the resting position. The quadrate swings backwards around 27 degrees. Amphikinesis is interpreted as allowing a stronger posterior recurvature of the maxillary teeth in Varanus. This increases the holding effect of the teeth without increasing their length, an adaptation of Varanus to capture relatively large prey. The formation of plicidentine (dentine infolding) in the teeth of Varanus increases the surface of attachment of the teeth on the supporting bone. Moreover, the dentine lamellae take up tensile and compressive stresses along their long axes upon axial or vertical loading of the teeth. The slope of pleurodonty is modelled so as to minimalize shear stress on the surface of ankylosis upon axial or vertical loading of the teeth.

Animals↗
PubMed1978

Plane penetration of uterine muscle by intrauterine shields.

A finite element approach is used to predict stress and deformation states of uterine muscle tissue under plane strain indentation by a flexible shield. Realistic, one-dimensional "punch" elements at the shield edges assure that muscle shear stresses remain bounded within experimentally measured values. For typical tissue, bearing pressure, deformation flow fields and edge slip stresses leading to tissue damage are calculated. Penetration depth to shield width ratios are up to 3.0. A piecewise linear, elastic approximation to the highly variable, nonlinear mechanical behavior of the tissue is used. Results are applied to the prediction of possible tissue damage by a flexible shield intrauterine contraceptive device, in place and in equilibrium with typical multiparous uteri.

Biomechanical Phenomena↗