Background Stent thrombosis (ST), a postinterventional complication with a mortality rate of 50%, has an incidence that rises precipitously in patients at risk. Chronic renal failure and end-stage renal disease have emerged as particularly strong ST risk factors, yet the mechanism remains elusive. Tissue factor (TF) is a crucial mediator of injury-related thrombosis and has been implicated for ST. We posit that uremia modulates TF in the local vessel wall to induce postinterventional thrombosis in patients with end-stage renal disease. Methods and Results As a model of the de-endothelialized, postinterventional state, we exposed primary human vascular smooth muscle cells (vSMCs) pretreated with uremic serum (obtained from ESRD patients on hemodialysis) to coronary-like blood flow. vSMC TF expression, activity, stability, and posttranslational modification were examined after vSMCs were treated with uremic serum or solutes. We found significantly greater clot formation after uremic serum exposure, which was substantially reduced with the prior treatment with anti-TF neutralizing antibody. Uremic sera induced 2- to 3-fold higher TF expression and activity in vSMCs independent of diabetes mellitus. Relevant concentrations of isolated uremic solutes such as indole-3-acetic acid (3.5 μg/mL), indoxyl sulfate (25 μg/mL), and uric acid (80 μg/mL) recapitulated these effects in cell culture and the flow loop model. We show further that TF undergoes ubiquitination at baseline and that uremic serum, indole-3-acetic acid, and indoxyl sulfate significantly prolong TF half-life by inhibiting its ubiquitination. Conclusions The uremic milieu is profoundly thrombogenic and upregulates vSMC TF levels by increasing TF stability and decreasing its ubiquitination. Together, these data demonstrate for the first time that the posttranslational regulation of TF in uremia may have a causative role in the increased ST risk observed in uremic patients. These data suggest that interventions that reduce vSMC TF may help to prevent ST and that uremic solutes should be considered as novel risk factors for ST in patients with chronic renal failure.

Background: Several E3 ligases regulate cytosolic ␤-catenin during Wnt-off phase. The fate of critical form active ␤-catenin in Wnt-on phase remains poorly defined. Results: Casitas B-lineage lymphoma (c-Cbl) ubiquitinates cytosolic ␤-catenin and translocates to the nucleus with Wnt induction to also ubiquitinate active nuclear ␤-catenin. Conclusion: c-Cbl is a unique E3 ligase targeting active nuclear ␤-catenin. Significance: This study uncovers a novel layer of Wnt regulation.

Microvascular endothelial cells at the blood-brain barrier exhibit a protective phenotype, which is highly induced by biochemical and biomechanical stimuli. Amongst them, shear stress enhances junctional tightness and limits transport at capillary-like levels. Abnormal flow patterns can reduce functional features of macrovascular endothelium. We now examine if this is true in brain microvascular endothelial cells. We suggest in this paper a complex response of endothelial cells to aberrant forces under different flow domains. Human brain microvascular endothelial cells were exposed to physiological or abnormal flow patterns. Physiologic shear (10-20 dyn/cm) upregulates expression of tight junction markers Zona Occludens 1 (1.7-fold) and Claudin-5 (more than 2-fold). High shear stress (40 dyn/cm) and/or pulsatility decreased their expression to basal levels and altered junctional morphology. We exposed cells to pathological shear stress patterns followed by capillary-like conditions. Results showed reversible recovery on the expression of tight junction markers. Flow protection of barrier phenotype commensurate with junctional signaling pathways decrease (Src, 0.25-fold, ERK, 0.77-fold) when compared to static conditions. This decrease was lost under high shear and pulsatile flow. In conclusion, abnormal shear stress inherent to systemic vascular disease leads to barrier impairment, which could be reverted by hemodynamic interventions.

Background: Carotid artery atherosclerotic stenosis is a preventable major cause of stroke, but there is still a need for definition of high-risk plaque in asymptomatic patients who might benefit from interventional therapies. Several image markers are recommended to characterize unstable plaques. The measurement of serum biomarkers is a promising method to assist in decision making, but the lack of robust evidence in the carotid environment burdens their potential as a standard of care. The goal of this review was to offer an updated state-of-the-art study of available serum biomarkers with clinical implications, with focus on those that may predict carotid symptom development. Methods: The Cochrane Library and MEDLINE databases were searched (all until September 2018) for studies on carotid plaque and serum biomarkers of atherosclerosis. Nonhuman, basic science, and histology studies were excluded, focusing on clinical studies. Selected abstracts were screened to include the most relevant articles on atherosclerotic plaque presence, progression, instability or symptom development. Results: Some well-established biomarkers for coronary disease are not relevant to carotid atherosclerosis and other inflammatory biomarkers, lipids, interleukins, homocysteine, and adipokines may be useful in quantifying carotid disease-related risk. Some serum biomarkers combined with image features may assist vascular specialists in selecting patients at high risk for stroke and in need of intervention. Conclusions: Prospective studies applying a combination of biomarkers are essential to prove clinical usefulness.

Background-Local modulation of vascular mammalian target of rapamycin (mTOR) signaling reduces smooth muscle cell (SMC) proliferation after endovascular interventions but may be associated with endothelial cell (EC) toxicity. The trilaminate vascular architecture juxtaposes ECs and SMCs to enable complex paracrine coregulation but shields SMCs from flow. We hypothesized that flow differentially affects mTOR signaling in ECs and SMCs and that SMCs regulate mTOR in ECs. Methods and Results-SMCs and/or ECs were exposed to coronary artery flow in a perfusion bioreactor. We demonstrated by flow cytometry, immunofluorescence, and immunoblotting that EC expression of phospho-S6 ribosomal protein (p-S6RP), a downstream target of mTOR, was doubled by flow. Conversely, S6RP in SMCs was growth factor but not flow responsive, and SMCs eliminated the flow sensitivity of ECs. Temsirolimus, a sirolimus analog, eliminated the effect of growth factor on SMCs and of flow on ECs, reducing p-S6RP below basal levels and inhibiting endothelial recovery. EC p-S6RP expression in stented porcine arteries confirmed our in vitro findings: Phosphorylation was greatest in ECs farthest from intact SMCs in metal stented arteries and altogether absent after sirolimus stent elution. Conclusions-The mTOR pathway is activated in ECs in response to luminal flow. SMCs inhibit this flow-induced stimulation of endothelial mTOR pathway. Thus, we now define a novel external stimulus regulating phosphorylation of S6RP and another level of EC-SMC crosstalk. These interactions may explain the impact of local antiproliferative delivery that targets SMC proliferation and suggest that future stents integrate design influences on flow and drug effects on their molecular targets. (Circulation. 2010;121:2192-2199.)Key Words: blood flow Ⅲ endothelium Ⅲ mammalian target of rapamycin (mTOR) Ⅲ molecular biology Ⅲ muscle, smooth Ⅲ signal transduction Ⅲ stents L ocal delivery of antiproliferative drugs limits the intimal hyperplastic response to vascular intervention but may place vessels at risk of thrombosis even late after initial treatment. The intervention, agents used, and means of administration can synergistically induce endothelial dysfunction and delay recovery, 1 leading to impaired vasoreactivity, enhanced platelet aggregation, 2 and elevated tissue factor expression. [3][4][5] Sirolimus, for example, inhibits smooth muscle cell (SMC) proliferation and intimal hyperplasia after vascular manipulation presumably through effects on signaling within the mammalian target of rapamycin (mTOR) pathway. mTOR is central to the regulation of protein synthesis, ribosomal protein translation, and cap-dependent translation, 6 and its inhibition with sirolimus alters the balance of mTORC1-mTORC2 complexes. 7 Prolonged exposure to sirolimus partially inhibits Akt activation and SMC proliferation. 8 However, sirolimus also induces tissue factor expression 3,4 and dysfunction in endothelial cells (ECs). The impact of flow and drug release on tissue drug distribution and va...

Flow drives variations in vascular reactivity and vascular beds. Endothelial health was preserved by arterial flow but jeopardized in regions of flow recirculation in a quasi-linear manner. Similarly, SMC exposed to flow were more thrombogenic in large recirculating regions. Health, thrombosis, and atherosclerosis biomarkers correlate with the extent of recirculation in vascular cells lining certain vascular geometries.

Cite this article: Pons R et al. 2020 Fluidstructure interaction simulations outperform computational fluid dynamics in the description of thoracic aorta haemodynamics and in the differentiation of progressive dilation in Marfan syndrome patients. R. Soc. open sci. 7: 191752. http://dx.

\bfA \bfb \bfs \bft \bfr \bfa \bfc \bft. The fluid-structure interaction (FSI) problem has received great attention in the last few years, mainly because it is present in many physical systems, industrial applications, and almost every biological system. In the parallel computational field, outstanding advances have been achieved for the individual components of the problem, allowing, for instance, simulations around complex geometries at very high Reynolds numbers or simulations of the contraction of a beating heart. However, it is not an easy task to combine the advances of both fields, given that they have followed development paths in a rather independent way, and also because physical and numerical instabilities arise when dealing with two highly nonlinear partial differential equations. Nonetheless, in the last few years great advances in the coupled FSI field have been achieved, recognizing the most challenging problems to tackle and enabling a new generation of numerical simulations in aerodynamics, biological systems, and complex industrial devices. Keeping in mind that efficient parallel codes for the individual components already exist, this paper presents a framework to build a massively parallel FSI solver in a multicode coupling partitioned approach, with strong focus in the parallel implementation aspects and the parallel performance of the resulting application. The problem is casted in an algebraic form, and the main points of interest are the parallel environment needed to be able to transfer data among the codes, the location of the exchange surface, and the exchange of information among the parallel applications. The proposed framework has been implemented in the HPC multiphysics code Alya, and the multicode coupling is carried out running separated instances of this code. Two coupling algorithms with different acceleration schemes are revised, and three representative cases of different areas of interest showing the reach of the proposed framework are solved. Good agreement with literature and experiments is obtained. In addition to the numerical validation of the FSI solver, an assessment of the parallel performance of the proposed multicode strategy is done. In particular, a special distribution of the fluid code and solid code MPI processes on the supercomputer nodes based on computing cores overloading is investigated. Finally, a strong scalability test, running up to a 30 million elements case using 1280 MPI processes, is done. \bfK \bfe \bfy \bfw \bfo \bfr \bfd \bfs. fluid-structure interaction, HPC, multicode coupling \bfA \bfM \bfS \bfs \bfu \bfb \bfj \bfe \bfc \bft \bfc \bfl \bfa \bfs \bfs \bfi fi\bfc \bfa \bft \bfi \bfo \bfn \bfs. 74F10, 68U20, 6804 \bfD \bfO \bfI. 10.1137/17M1138868 1. Introduction. Fluid-structure interaction (FSI) governs so many physical problems, industrial devices, and biological systems that its relevance is out of the question. FSI combines the challenges of computational fluid dynamics (CFD) with those of computational solid dynamics (CSD).