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BACKGROUND: Human dental pulp stem cells represent a mesenchymal stem cell niche localized in the perivascular area of dental pulp and are characterized by low immunogenicity and immunomodulatory/anti-inflammatory properties. Pericytes, mural cells surrounding the endothelium of small vessels, regulate numerous functions including vessel growth, stabilization and permeability. It is well established that pericytes have a tight cross talk with endothelial cells in neoangiogenesis and vessel stabilization, which are regulated by different factors, i.e., microenvironment and flow-dependent shear stress. The aim of this study was to evaluate the effects of a pulsatile unidirectional flow in the presence or not of an inflammatory microenvironment on the biological properties of pericyte-like cells isolated from human dental pulp (hDPSCs). METHODS: Human DPSCs were cultured under both static and dynamic conditions with or without pre-activated peripheral blood mononuclear cells (PBMCs). Pulsatile unidirectional flow shear stress was generated by using a specific peristaltic pump. The angiogenic potential and inflammatory properties of hDPSCs were evaluated through reverse phase protein microarrays (RPPA), confocal immunofluorescence and western blot analyses. RESULTS: Our data showed that hDPSCs expressed the typical endothelial markers, which were up-regulated after endothelial induction, and were able to form tube-like structures. RPPA analyses revealed that these properties were modulated when a pulsatile unidirectional flow shear stress was applied to hDPSCs. Stem cells also revealed a downregulation of the immune-modulatory molecule PD-L1, in parallel with an up-regulation of the pro-inflammatory molecule NF-kB. Immune-modulatory properties of hDPSCs were also reduced after culture under flow-dependent shear stress and exposure to an inflammatory microenvironment. This evidence was strengthened by the detection of up-regulated levels of expression of pro-inflammatory cytokines in PBMCs. CONCLUSIONS: In conclusion, the application of a pulsatile unidirectional flow shear stress induced a modulation of immunomodulatory/inflammatory properties of dental pulp pericyte-like cells.

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The water channel aquaporin-1 (AQP1) is the principal water pathway for isotonic water reabsorption in the kidney proximal tubule (PT). We investigated flow-mediated fluid (Jv) and [Formula: see text] ([Formula: see text]) reabsorption in PTs of the mouse kidney by microperfusion in wild-type (WT) and AQP1 knockout (KO) mice. Experiments were simulated in an adaptation of a mathematical model of the rat PT. An increase in perfusion rate from 5 to 20 nL/min increased Jv and [Formula: see text] in PTs of WT mice. AQP1 KO mice significantly decreased Jv at low and high flow rates compared with control. In contrast, [Formula: see text] was not reduced at either low or high flow rates. Cell volume showed no significant difference between WT and AQP1 KO mice. Renal clearance experiments showed significantly higher urine flow in AQP1 KO mice, but there was no significant difference in either Na+ and K+ or [Formula: see text] excretion. Acid-base parameters of blood pH, Pco2, [Formula: see text], and urine pH were the same in both WT and KO mice. In model calculations, tubules whose tight junction (TJ) water permeability (Pf) was that assigned to the rat TJ, showed no difference in Jv between WT and KO, whereas TJ Pf set to 25% of the rat predicted Jv concordant with our observations from AQP1 KO. These results affirm the dominance of AQP1 in mediating isotonic water reabsorption by the mouse PT and demonstrate that flow-stimulated [Formula: see text] reabsorption is intact and independent of AQP1. With reference to the model, the findings also suggest that TJ water flux in the PT is less prominent in the mouse than in the rat kidney.NEW & NOTEWORTHY We found an absence of flow-dependent modulation of fluid absorption but no effect on either proximal tubule (PT) [Formula: see text] absorption or acid-base parameters in the aquaporin 1 (AQP1) knockout mouse. We affirmed the dominance of the water channel AQP1 in mediating isotonic water reabsorption by the mouse PT and demonstrated that flow-stimulated [Formula: see text] reabsorption is independent of AQP1. With reference to the model, the findings also suggest that tight junctional water flux in the PT is less prominent in the mouse than rat kidney.

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OBJECTIVE: The study was designed to investigate the role of exercise in ameliorating endothelial function and hemodynamics in postmenopausal females, and compare the different effects of high-intensity interval training and moderate-intensity continuous training by equalizing training load. DESIGN: Randomized controlled trial. METHODS: First intervention, 30 volunteers were randomized into low-intensity continuous training group or sedentary group. The low-intensity continuous training group was assigned to a 12-week training program at an intensity of 40% maximum heart reserve. The second intervention was an 8-week training program, in which 18 individuals were randomly placed either in the moderate-intensity continuous training or high-intensity interval training group. Flow-mediated dilatation, blood samples, carotid ultrasound, and wall shear stress were collected before, during, and after the interventions. RESULTS: Flow-mediated dilatation was significantly increased in low-intensity continuous training group (p = 0.02), moderate-intensity continuous training (p = 0.023) and high-intensity interval training (p < 0.01) groups, with a time × group interaction for %FMD (F2, 32 = 4.421, p = 0.02), and a main effect of time (F2, 32 = 27.658, p < 0.001). Nitric oxide in low-intensity continuous training increased remarkably (p = 0.024) and was higher than that in control (p = 0.011). High-intensity interval training (p < 0.001) and moderate-intensity continuous training (p < 0.001) increased nitric oxide. Endothelin was decreased only in high-intensity interval training group (p = 0.049). All the training programs had a remarkable impact on wall shear stress. CONCLUSIONS: Low-intensity continuous training can improve endothelial function in postmenopausal females. High-intensity interval training could be an effective training regimen for improving endothelial function than moderate-intensity continuous training in postmenopausal females.

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PURPOSE: To study the reactivity of the vascular endothelium and the elastic properties of the upper and lower extremities, and assess the vascular innervation effect of Cytoflavin in patients with stable and rapidly progressive primary open-angle glaucoma (POAG). MATERIAL AND METHODS: The study included 67 patients with POAG (mean age 66.3±1.5 years), among them 31 with stable and 36 with rapidly progressive glaucoma. During the first stage of the study, the reactivity of the vascular endothelium was assessed with reactive hyperemia test; the viscoelastic properties of the upper and lower extremities were evaluated using volumetric sphygmomanometry. For the second stage of the study, patients were divided into the main group (n=20) that received intravenous injections of 10 ml Cytoflavin with 200 ml of 5% glucose solution for 10 days and then 2 tablets twice a day for 60 days, and the control group (n=16). RESULTS: The function of the vascular endothelium was significantly reduced in patients with rapidly progressive POAG. Correlation analysis revealed a negative correlation between the flow-dependent vasodilation (FDV), and the duration of POAG and initial diameter of the brachial artery (r=0.5, p<0.05 and r=0.6, p<0.05, respectively). Pathological response of vessel endothelium was detected in 88% of patients with stable and 96% of patients with rapidly progressive POAG. Cytoflavin was found to have positive effects on the endothelium in patients with POAG. CONCLUSION: The obtained data can be used for identification of risk factors for rapid POAG progression and optimization of its treatment.

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The preservation of life history and other phenotypic complexity is central to the resilience of Pacific salmon stocks. Steelhead (Oncorhynchus mykiss) express a diversity of life-history strategies such as the propensity to migrate (anadromy/residency) and the timing and state of maturation upon return to freshwater (run-timing), providing an opportunity to study adaptive phenotypic complexity. Historically, the Eel River supported upwards of 1 million salmon and steelhead, but the past century has seen dramatic declines of all salmonids in the watershed. Here we investigate life-history variation in Eel River steelhead by using Rapture sequencing, on thousands of individuals, to genotype the region diagnostic for run-timing (GREB1L) and the region strongly associated with residency/anadromy (OMY5) in the Eel River and other locations, as well as determine patterns of overall genetic differentiation. Our results provide insight into many conservation-related issues. For example, we found that distinct segregation between winter and summer-run steelhead correlated with flow-dependent barriers in major forks of the Eel, that summer-run steelhead inhabited the upper Eel prior to construction of an impassable dam, and that both life history and overall genetic diversity have been maintained in the resident trout population above; and we found no evidence of the summer-run allele in the South Fork Eel, indicating that summer run-timing cannot be expected to arise from standing genetic variation in this and other populations that lack the summer-run phenotype. The results presented in this study provide valuable information for designing future restoration and management strategies for O. mykiss in Northern California and beyond.

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Metastatic spine disease (MSD) is a severe event in cancer patients. Experimental data indicate that bone metastasis is mostly mediated by blood flow-dependent, passive arrest of circulating tumor cells to the bone metastatic niche (BMN). Here, we have set out to test these experimental observations in a clinical, human setting to improve our understanding of MSD. 507 patients, treated on spinal metastases in our institution from 2005 to 2015 were retrospectively evaluated. We identified 259 patients with accessible staging reports of the skeleton before and at initial diagnosis of MSD. Data analysis comprised localizations of bone metastases, underlying malignancy and time to development of MSD. Dissemination pattern of bone metastasis was correlated with red bone marrow (RBM) content of the respective bone as a measure of blood flow. Spinal metastases occurred most frequently in lung cancer (21%), prostate cancer (19%), and breast cancer (12%). At the diagnosis of MSD, majority of patients have multiple extra-spinal bone metastases (2/3). The distribution of metastases to extra-spinal bones and to the spine is mostly proportional to the RBM content of the involved bone. Corresponding to the high RBM content, thoracic spine, pelvic bones and ribs represent a predilection site for bone metastasis. We confirm a distinct preference of cancer types to metastasize to bones. When it comes to bone metastases all primaries show uniform distribution pattern, which supports the hypothesis of a predominantly blood flow-dependent distribution of tumor cells and passive arrest to the BMN rather than a spine-specific homing mechanism.

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The purpose of this review is to summarize our knowledge and understanding of the physiological importance and the mechanisms underlying flow-activated proximal tubule transport. Since the earliest micropuncture studies of mammalian proximal tubule, it has been recognized that tubular flow is an important regulator of sodium, potassium, and acid-base transport in the kidney. Increased fluid flow stimulates Na+ and HCO3- absorption in the proximal tubule via stimulation of Na/H-exchanger isoform 3 (NHE3) and H+-ATPase. In the proximal tubule, brush border microvilli are the major flow sensors, which experience changes in hydrodynamic drag and bending moment as luminal flow velocity changes and which transmit the force of altered flow to cytoskeletal structures within the cell. The signal to NHE3 depends upon the integrity of the actin cytoskeleton; the signal to the H+-ATPase depends upon microtubules. We have demonstrated that alterations in fluid drag impact tubule function by modulating ion transporter availability within the brush border membrane of the proximal tubule. Beyond that, there is evidence that transporter activity within the peritubular membrane is also modulated by luminal flow. Secondary messengers that regulate the flow-mediated tubule function have also been delineated. Dopamine blunts the responsiveness of proximal tubule transporters to changes in luminal flow velocity, while a DA1 antagonist increases flow sensitivity of solute reabsorption. IP3 receptor-mediated intracellular Ca2+ signaling is critical to transduction of microvillus drag. In this review, we summarize our findings of the regulatory mechanism of flow-mediated Na+ and HCO3- transport in the proximal tubule and review available information about flow sensing and regulatory mechanism of glomerulotubular balance.

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PURPOSE: To prospectively compare 3D flow-dependent subtractive MRA vs. 2D flow-independent non-subtractive MRA for assessment of the calf arteries at 3 Tesla. METHODS: Forty-two patients with peripheral arterial occlusive disease underwent nonenhanced MRA of calf arteries at 3 Tesla with 3D flow-dependent subtractive MRA (fast spin echo sequence; 3D-FSE-MRA) and 2D flow-independent non-subtractive MRA (balanced steady-state-free-precession sequence; 2D-bSSFP-MRA). Moreover, all patients underwent contrast-enhanced MRA (CE-MRA) as standard-of-reference. Two readers performed a per-segment evaluation for image quality (4 = excellent to 0 = non-diagnostic) and severity of stenosis. RESULTS: Image quality scores of 2D-bSSFP-MRA were significantly higher compared to 3D-FSE-MRA (medians across readers: 4 vs. 3; p < 0.0001) with lower rates of non-diagnostic vessel segments on 2D-bSSFP-MRA (reader 1: <1 % vs. 15 %; reader 2: 1 % vs. 29 %; p < 0.05). Diagnostic performance of 2D-bSSFP-MRA and 3D-FSE-MRA across readers showed sensitivities of 89 % (214/240) vs. 70 % (168/240), p = 0.0153; specificities: 91 % (840/926) vs. 63 % (585/926), p < 0.0001; and diagnostic accuracies of 90 % (1054/1166) vs. 65 % (753/1166), p < 0.0001. CONCLUSION: 2D flow-independent non-subtractive MRA (2D-bSSFP-MRA) is a robust nonenhanced MRA technique for assessment of the calf arteries at 3 Tesla with significantly higher image quality and diagnostic accuracy compared to 3D flow-dependent subtractive MRA (3D-FSE-MRA). KEY POINTS: • 2D flow-independent non-subtractive MRA (2D-bSSFP-MRA) is a robust NE-MRA technique at 3T • 2D-bSSFP-MRA outperforms 3D flow-dependent subtractive MRA (3D-FSE-MRA) as NE-MRA of calf arteries • 2D-bSSFP-MRA is a promising alternative to CE-MRA for calf PAOD evaluation.

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Flow-modulated salt and water transport in proximal tubules has been recognized for more than four decades. Recent work has made major progress in defining the underlying cellular mechanisms. First, we demonstrated that perfusion-absorption balance is present in the isolated perfused proximal tubule of the mouse kidney, and thus is independent of neuronal control and systemic hormonal regulation. In proximal tubule, higher axial flow rates stimulate sodium and bicarbonate absorption by increased apical membrane Na+/H+-transporter and H-ATPase activity. It is also evident that fluid shear stress stimulates Na+/H+ exchanger isoform 3 (NHE3) exocytosis and trafficking to the apical membrane of the proximal tubule cells. Second, experimental data and modeling calculations provide strong evidence that brush border microvilli function as flow sensors in the proximal tubule. Flow-induced changes of proximal tubule absorption depend on the changes of torque (bending moment) on the microvilli, and that an intact actin cytoskeleton is required to transduce signals from the brush border to cell and alter transport activity, NHE3 expression and trafficking. Third, the increased NHE3 exocytosis by dopamine blockers enhanced tubule sensitivity to torque, and the IP3 receptor-mediated intracellular Ca2+ signaling is a critical step in transduction of fluid drag on microvillus drag tips in modulating Na+ and HCO3 - transport. Finally, in all of our experimental studies, flow-dependent transport in mouse tubules was achieved with virtually no change in tubule cell volume. Our model calculations suggest that this observation is strong evidence for proportional luminal and peritubular effects of flow on transporter density.

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Subsurface lateral flow in both texture-contrast soils and catchments with shallow bedrock is suspected to be a non-point source of contamination of watercourses by pesticides used in agriculture. As a case study, the north of the Beaujolais region (eastern France) provides a favorable environment for such contamination due to its agro-pedo-climatic conditions. Environments seen in the Beaujolais region include intense viticulture, permeable and shallow soils, steep hillslopes, and storms that occur during the periods of pesticide application. Watercourse contamination by pesticides has been widely observed in this region, and offsite pesticide transport by subsurface lateral flow is suspected to be involved in diffuse and chronic presence of pesticides in surface water. In order to confirm and quantify the potential role of such processes in pesticide transfer, an automated trench system has been designed. The trench was set up on a steep farmed hillslope in a texture-contrast soil. It was equipped with a tipping bucket flow meter and an automatic sampler to monitor pesticide concentrations in lateral flow at fine resolution, by means of a flow-dependent sampling strategy. Four pesticides currently used in vine growing were studied to provide a range of mobility properties: one insecticide (chlorpyrifos-methyl) and three fungicides (spiroxamine, tebuconazole, and dimethomorph). With this system, it was possible to study pesticide concentration dynamics in the subsurface lateral flow, generated by substantial rainfall events following pesticide applications. The experimental design ascertained to be a suitable method in which to monitor subsurface lateral flow and related transfer of pesticides.

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In the proximal tubule, axial flow (drag on brush-border microvilli) stimulates Na(+) and HCO3 (-) reabsorption by modulating both Na/H exchanger 3 (NHE3) and H-ATPase activity, a process critical to glomerulotubular balance. We have also demonstrated that blocking the angiotensin II receptor decreases baseline transport, but preserves the flow effect; dopamine leaves baseline fluxes intact, but abrogates the flow effect. In the current work, we provide evidence implicating cytosolic calcium in flow-dependent transport. Mouse proximal tubules were microperfused in vitro at perfusion rates of 5 and 20 nl/min, and reabsorption of fluid (Jv) and HCO3 (-) (JHCO3) were measured. We examined the effect of high luminal Ca(2+) (5 mM), 0 mM Ca(2+), the Ca(2+) chelator BAPTA-AM, the inositol 1,4,5-trisphosphate (IP3) receptor antagonist 2-aminoethoxydiphenyl borate (2-APB), and the Ca-ATPase inhibitor thapsigargin. In control tubules, increasing perfusion rate from 5 to 20 nl/min increased Jv by 62% and JHCO3 by 104%. With respect to Na(+) reabsorption, high luminal Ca(2+) decreased transport at low flow, but preserved the flow-induced increase; low luminal Ca(2+) had little impact; both BAPTA and 2-APB had no effect on baseline flux, but abrogated the flow effect; thapsigargin decreased baseline flow, leaving the flow effect intact. With respect to HCO3 (-) reabsorption, high luminal Ca(2+) decreased transport at low flow and mildly diminished the flow-induced increase; low luminal Ca(2+) had little impact; both BAPTA and 2-APB had no effect on baseline flux, but abrogated the flow effect. These data implicate IP3 receptor-mediated intracellular Ca(2+) signaling as a critical step in transduction of microvillous drag to modulate Na(+) and HCO3 (-) transport.

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Coronary heart disease causes obstruction of coronary blood flow and is the leading cause of death worldwide. The effect of focal stenosis on downstream flow pattern in the coronary arterial tree is not well understood. Here, the blood flows in normal and diseased porcine left anterior descending (LAD) arterial tree were modeled and compared to determine the effects of stenosis on the blood flow distribution and hemodynamic parameters. The anatomical model of LAD was extracted from a porcine heart by computed tomography (CT), which was comprised of a main trunk and nine side branches. Stenoses with various severities were imposed into the main trunk between the first and second side branches, and the boundary condition at each outlet accounted for the effect of stenosis on the flow rate in the downstream vasculature. It was found that only significant stenosis (≥75% area reduction) considerably altered pressure drop and total flow rate distribution in branches and at each bifurcation. The effect of significant stenosis on bifurcations, however, diminished at downstream locations. As demonstrated by distributions of oscillatory shear index and relative residence time, non-significant stenosis (<75% area reduction) has the potential to induce atherosclerosis near the ostium of downstream side branch, while significant stenosis can promote atherosclerosis in its wake.

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Professor Tudor Griffith was one of the founding members of the European Study Group on Cardiovascular Oscillations, and hosted the 1st ESGCO Conference in Cardiff, Wales in 2000. Tudor was a passionate scientist, who managed to combine his enthusiasm for vascular biology with his background in physics, to make key and insightful advances to our knowledge and understanding of the integrated vascular control mechanisms that co-ordinate blood flow in tissue perfusion. He had a particular interest in the endothelium, the monolayer of cells that lines the entire cardiovascular system and which is in prime position to sense a wide variety of modulatory stimuli, both chemical and mechanical. Over the last 20 years Tudor produced a series of research papers in which he used chaos theory to analyse the behaviour of arteries that underpins vasomotion. The research led to the development of mathematical models that were able to predict calcium oscillations in vascular smooth muscle with a view to predicting events in a complete virtual artery. This article will review the field in which he worked, with an obvious emphasis on his contribution.

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BACKGROUND: There are limited indications for superficial temporal artery to middle cerebral artery (STA-MCA) bypass in the treatment of cerebral atherosclerotic disease. However, recent reports emphasize that STA-MCA bypass may be beneficial for select patients. In this report, we describe a case in which a flow-dependent STA-MCA bypass was achieved in a patient with unstable internal carotid artery (ICA) stenosis. CASE DESCRIPTION: A 51-year-old woman presented with left ICA occlusion. A severely elongated mean transit time (MTT) indicated misery perfusion. STA-MCA bypass was performed immediately and blood flow through the graft appeared excellent on magnetic resonance angiography (MRA). Two weeks later, MRA revealed normal anterograde ICA blood flow and the bypass graft was not visible. Three years later, the left ICA stenosis again became severe and the patient developed contralateral hemiparesis. She underwent endovascular surgery and the ipsilateral MCA became occluded during the procedure. The STA-MCA bypass graft appeared immediately after the MCA occlusion and became a major provider of blood flow to the ipsilateral MCA area. She recovered with almost no deficit. CONCLUSION: This is a rare case which shows that dynamic flow changes through an STA-MCA bypass can occur with variable ICA blood flow. STA-MCA bypass can be beneficial for the treatment of unstable ICA stenosis.

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Surgical removal of bone metastasis from hepatocellular carcinoma frequently produces profuse bleeding. To reduce bleeding, we have performed preoperative embolization of tumor feeding artery with flow-dependent micro-platinum coils during superselective angiography in a case of frontal bone metastasis from hepatocellular carcinoma. The tumor was removed easily with minimal bleeding after the embolization, so we report the case with review of the relevant literature.

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