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Dive into the research topics where Sarah Hsiao is active.

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Featured researches published by Sarah Hsiao.


Arteriosclerosis, Thrombosis, and Vascular Biology | 2014

Disturbed Flow Promotes Endothelial Senescence via a p53-Dependent Pathway

Christina M. Warboys; Amalia de Luca; Narges Amini; Le Luong; Hayley Duckles; Sarah Hsiao; Alex White; Shukti Biswas; Ramzi Khamis; Chuh K. Chong; Wai-Mun Cheung; Spencer J. Sherwin; Martin R. Bennett; Jesús Gil; Justin C. Mason; Dorian O. Haskard; Paul C. Evans

Objective—Although atherosclerosis is associated with systemic risk factors such as age, high cholesterol, and obesity, plaque formation occurs predominately at branches and bends that are exposed to disturbed patterns of blood flow. The molecular mechanisms that link disturbed flow–generated mechanical forces with arterial injury are uncertain. To illuminate them, we investigated the effects of flow on endothelial cell (EC) senescence. Approach and Results—LDLR−/− (low-density lipoprotein receptor−/−) mice were exposed to a high-fat diet for 2 to 12 weeks (or to a normal chow diet as a control) before the assessment of cellular senescence in aortic ECs. En face staining revealed that senescence-associated &bgr;-galactosidase activity and p53 expression were elevated in ECs at sites of disturbed flow in response to a high-fat diet. By contrast, ECs exposed to undisturbed flow did not express senescence-associated &bgr;-galactosidase or p53. Studies of aortae from healthy pigs (aged 6 months) also revealed enhanced senescence-associated &bgr;-galactosidase staining at sites of disturbed flow. These data suggest that senescent ECs accumulate at disturbed flow sites during atherogenesis. We used in vitro flow systems to examine whether a causal relationship exists between flow and EC senescence. Exposure of cultured ECs to flow (using either an orbital shaker or a syringe-pump flow bioreactor) revealed that disturbed flow promoted EC senescence compared with static conditions, whereas undisturbed flow reduced senescence. Gene silencing studies demonstrated that disturbed flow induced EC senescence via a p53-p21 signaling pathway. Disturbed flow–induced senescent ECs exhibited reduced migration compared with nonsenescent ECs in a scratch wound closure assay, and thus may be defective for arterial repair. However, pharmacological activation of sirtuin 1 (using resveratrol or SRT1720) protected ECs from disturbed flow–induced senescence. Conclusions—Disturbed flow promotes endothelial senescence via a p53-p21–dependent pathway which can be inhibited by activation of sirtuin 1. These observations support the principle that pharmacological activation of sirtuin 1 may promote cardiovascular health by suppressing EC senescence at atheroprone sites.


Heart | 2016

Computational fluid dynamics modelling in cardiovascular medicine

Paul Morris; A. J. Narracott; Hendrik von Tengg-Kobligk; Daniel Alejandro Silva Soto; Sarah Hsiao; Angela Lungu; Paul C. Evans; Neil W. Bressloff; Patricia V. Lawford; D. Rodney Hose; Julian Gunn

This paper reviews the methods, benefits and challenges associated with the adoption and translation of computational fluid dynamics (CFD) modelling within cardiovascular medicine. CFD, a specialist area of mathematics and a branch of fluid mechanics, is used routinely in a diverse range of safety-critical engineering systems, which increasingly is being applied to the cardiovascular system. By facilitating rapid, economical, low-risk prototyping, CFD modelling has already revolutionised research and development of devices such as stents, valve prostheses, and ventricular assist devices. Combined with cardiovascular imaging, CFD simulation enables detailed characterisation of complex physiological pressure and flow fields and the computation of metrics which cannot be directly measured, for example, wall shear stress. CFD models are now being translated into clinical tools for physicians to use across the spectrum of coronary, valvular, congenital, myocardial and peripheral vascular diseases. CFD modelling is apposite for minimally-invasive patient assessment. Patient-specific (incorporating data unique to the individual) and multi-scale (combining models of different length- and time-scales) modelling enables individualised risk prediction and virtual treatment planning. This represents a significant departure from traditional dependence upon registry-based, population-averaged data. Model integration is progressively moving towards ‘digital patient’ or ‘virtual physiological human’ representations. When combined with population-scale numerical models, these models have the potential to reduce the cost, time and risk associated with clinical trials. The adoption of CFD modelling signals a new era in cardiovascular medicine. While potentially highly beneficial, a number of academic and commercial groups are addressing the associated methodological, regulatory, education- and service-related challenges.


Cardiovascular Research | 2013

The effects of stenting on shear stress: relevance to endothelial injury and repair

Kim Van der Heiden; Frank J. H. Gijsen; A. J. Narracott; Sarah Hsiao; Ian Halliday; Julian Gunn; Jolanda J. Wentzel; Paul C. Evans

Stent deployment following balloon angioplasty is used routinely to treat coronary artery disease. These interventions cause damage and loss of endothelial cells (EC), and thus promote in-stent thrombosis and restenosis. Injured arteries are repaired (intrinsically) by locally derived EC and by circulating endothelial progenitor cells which migrate and proliferate to re-populate denuded regions. However, re-endothelialization is not always complete and often dysfunctional. Moreover, the molecular and biomechanical mechanisms that control EC repair and function in stented segments are poorly understood. Here, we propose that stents modify endothelial repair processes, in part, by altering fluid shear stress, a mechanical force that influences EC migration and proliferation. A more detailed understanding of the biomechanical processes that control endothelial healing would provide a platform for the development of novel therapeutic approaches to minimize damage and promote vascular repair in stented arteries.


Scientific Reports | 2017

Shear stress induces endothelial-to-mesenchymal transition via the transcription factor Snail

Marwa Mahmoud; Shuang Feng; Céline Souilhol; Rouyu Xing; Sarah Hsiao; Akiko Mammoto; Jing Chen; Markus Ariaans; Sheila E. Francis; Kim Van der Heiden; Victoria Ridger; Paul C. Evans

Blood flow influences atherosclerosis by generating wall shear stress, which alters endothelial cell (EC) physiology. Low shear stress induces dedifferentiation of EC through a process termed endothelial-to-mesenchymal transition (EndMT). The mechanisms underlying shear stress-regulation of EndMT are uncertain. Here we investigated the role of the transcription factor Snail in low shear stress-induced EndMT. Studies of cultured EC exposed to flow revealed that low shear stress induced Snail expression. Using gene silencing it was demonstrated that Snail positively regulated the expression of EndMT markers (Slug, N-cadherin, α-SMA) in EC exposed to low shear stress. Gene silencing also revealed that Snail enhanced the permeability of endothelial monolayers to macromolecules by promoting EC proliferation and migration. En face staining of the murine aorta or carotid arteries modified with flow-altering cuffs demonstrated that Snail was expressed preferentially at low shear stress sites that are predisposed to atherosclerosis. Snail was also expressed in EC overlying atherosclerotic plaques in coronary arteries from patients with ischemic heart disease implying a role in human arterial disease. We conclude that Snail is an essential driver of EndMT under low shear stress conditions and may promote early atherogenesis by enhancing vascular permeability.


Circulation Research | 2016

TWIST1 Integrates Endothelial Responses to Flow in Vascular Dysfunction and Atherosclerosis

Marwa Mahmoud; H.R. Kim; Rouyu Xing; Sarah Hsiao; Akiko Mammoto; Jing Chen; Shuang Feng; Neil Bowden; Richard Maguire; Markus Ariaans; Sheila E. Francis; Peter D. Weinberg; Kim Van der Heiden; Elizabeth A.V. Jones; Timothy J. A. Chico; Victoria Ridger; Paul C. Evans

Supplemental Digital Content is available in the text.


Arteriosclerosis, Thrombosis, and Vascular Biology | 2017

Mechanical Activation of Hypoxia-Inducible Factor 1α Drives Endothelial Dysfunction at Atheroprone Sites

Shuang Feng; Neil Bowden; Maria Fragiadaki; Céline Souilhol; Sarah Hsiao; Marwa Mahmoud; Scott P. Allen; Daniela Pirri; Blanca Tardajos Ayllon; Shamima Akhtar; A.A. Roger Thompson; Hanjoong Jo; Christian Weber; Victoria Ridger; Andreas Schober; Paul C. Evans

Objective— Atherosclerosis develops near branches and bends of arteries that are exposed to low shear stress (mechanical drag). These sites are characterized by excessive endothelial cell (EC) proliferation and inflammation that promote lesion initiation. The transcription factor HIF1&agr; (hypoxia-inducible factor 1&agr;) is canonically activated by hypoxia and has a role in plaque neovascularization. We studied the influence of shear stress on HIF1&agr; activation and the contribution of this noncanonical pathway to lesion initiation. Approach and Results— Quantitative polymerase chain reaction and en face staining revealed that HIF1&agr; was expressed preferentially at low shear stress regions of porcine and murine arteries. Low shear stress induced HIF1&agr; in cultured EC in the presence of atmospheric oxygen. The mechanism involves the transcription factor nuclear factor-&kgr;B that induced HIF1&agr; transcripts and induction of the deubiquitinating enzyme Cezanne that stabilized HIF1&agr; protein. Gene silencing revealed that HIF1&agr; enhanced proliferation and inflammatory activation in EC exposed to low shear stress via induction of glycolysis enzymes. We validated this observation by imposing low shear stress in murine carotid arteries (partial ligation) that upregulated the expression of HIF1&agr;, glycolysis enzymes, and inflammatory genes and enhanced EC proliferation. EC-specific genetic deletion of HIF1&agr; in hypercholesterolemic apolipoprotein E–defecient mice reduced inflammation and endothelial proliferation in partially ligated arteries, indicating that HIF1&agr; drives inflammation and vascular dysfunction at low shear stress regions. Conclusions— Mechanical low shear stress activates HIF1&agr; at atheroprone regions of arteries via nuclear factor-&kgr;B and Cezanne. HIF1&agr; promotes atherosclerosis initiation at these sites by inducing excessive EC proliferation and inflammation via the induction of glycolysis enzymes.


Antioxidants & Redox Signaling | 2016

Experimental Approaches to Study Endothelial Responses to Shear Stress

Neil Bowden; Matthew T. Bryan; Hayley Duckles; Shuang Feng; Sarah Hsiao; H.R. Kim; Marwa Mahmoud; Britta Moers; Ioannis Xanthis; Victoria Ridger; Paul C. Evans

SIGNIFICANCE Shear stress controls multiple physiological processes in endothelial cells (ECs). RECENT ADVANCES The response of ECs to shear has been studied using a range of in vitro and in vivo models. CRITICAL ISSUES This article describes some of the experimental techniques that can be used to study endothelial responses to shear stress. It includes an appraisal of large animal, rodent, and zebrafish models of vascular mechanoresponsiveness. It also describes several bioreactors to apply flow to cells and physical methods to separate mechanoresponses from mass transport mechanisms. FUTURE DIRECTIONS We conclude that combining in vitro and in vivo approaches can provide a detailed mechanistic view of vascular responses to force and that high-throughput systems are required for unbiased assessment of the function of shear-induced molecules. Antioxid. Redox Signal. 25, 389-400.


Heart | 2014

189 Disturbed Flow Promotes Endothelial Cell Injury Via the Induction of Developmental Genes

Marwa Mahmoud; Rosemary Kim; Amalia de Luca; Ismael Gauci; Sarah Hsiao; Paul C. Evans

Introduction Atherosclerosis, a disease of arteries that can cause heart attack and stroke, is influenced by local blood flow patterns which exert wall shear stress (WSS) on endothelial cells (EC). Low, oscillatory WSS (LWSS) promotes atherosclerosis by inducing EC apoptosis and activation, while high, unidirectional WSS (HWSS) is athero-protective. We recently used microarray technology coupled to computational fluid dynamics to study the transcriptome of EC at regions of the porcine aorta exposed to LWSS or HWSS. The study revealed differential expression of multiple genes (GATA4, HAND2, TWIST1, FZD5, BMP2, SLIT2, PDGFRA, FBN2 and GJA5) that co-ordinate embryonic development. We hypothesised that this gene set includes regulators of EC survival in response to haemodynamic forces. Methods EC were isolated from inner (LWSS) and outer (HWSS) curvatures of the porcine aortic arch using collagenase and the expression of particular developmental genes was determined using quantitative RT-PCR (n = 6). The expression of GATA4 in the murine aorta was assessed at the protein level by en face fluorescent staining and confocal microscopy (n = 5). Porcine aortic EC (n = 7) or human umbilical vein EC (n = 7) were exposed to flow using an orbiting 6-well plate (210 rpm) which generates LWSS (centre) and HWSS (periphery). Alternatively, cells were exposed to LWSS or HWSS using an IBIDI™ pump system (n = 3). The expression of specific developmental genes was determined by quantitative RT-PCR. Developmental genes were silenced in sheared EC using two different gene-specific siRNA sequences prior to assessment of apoptosis using antibodies that recognise active caspase-3 (n = 3). Results Quantitative RT-PCR revealed that the expression of multiple developmental genes (GATA4, HAND2, TWIST1, FZD5, BMP2, SLIT2, PDGFRA, and FBN2) was elevated at the LWSS compared to the HWSS region of the porcine aorta (p < 0.05). Similarly, en face staining demonstrated that expression of GATA4 protein in EC was higher at a LWSS compared to a HWSS site of the murine aortic arch (p < 0.05). GATA4, HAND2, TWIST1, FZD5, BMP2, SLIT2, PDGFRA, and FBN2 were induced in HUVEC or PAEC exposed to LWSS for 72 h using either the orbital or IBIDI™ systems (p < 0.05). The rate of caspase-3 activation was significantly higher in EC exposed to LWSS compared to HWSS (3.1% vs 0.7%; p < 0.0001; n = 10). Silencing of GATA4, FZD5 and BMP2 significantly reduced apoptosis in EC exposed to LWSS (1.2%, 0.6% and 1.6%; p < 0.05). Conclusions We conclude that LWSS promotes EC apoptosis via a mechanism that involves the induction of GATA4, FZD5 and BMP2; molecules that have a well-defined role in embryonic development. Further work is required to define the molecular mechanisms that underly the induction of apoptosis by these molecules. Our observations illuminate the molecular mechanisms that regulate the focal nature of vascular injury and atherosclerosis.


Heart | 2015

204 Disturbed Flow Promotes Atherogenesis through the Activation of Endothelial-Mesenchymal Transition

Marwa Mahmoud; Rosemary Kim; Sarah Hsiao; Ruoyu Xing; Kim Van der Heiden; Akiko Mammoto; Jing Chen; Ismael Gauci; Shuang Feng; Paul C. Evans

Introduction Atherosclerosis is influenced by local blood flow patterns, which exert wall shear stress (WSS) on endothelial cells (EC). Low, oscillatory WSS promotes atherosclerosis by inducing EC proliferation and permeability, while high WSS is athero-protective. We recently used microarray technology coupled to computational fluid dynamics to study the transcriptome of EC at regions of the porcine aorta exposed to low, oscillatory or high, unidirectional WSS. The study revealed differential expression of GATA4 and Twist1. These transcription factors can promote endothelial-mesenchymal transition (EndMT), a process that involves altered vascular endothelial (VE)- cadherin function and enhanced EC proliferation. Here we tested the hypothesis that GATA4 and Twist1 may promote atherogenesis at sites of disturbed flow by inducing EndMT. Methods and results Quantitative RT-PCR and en face staining confirmed elevated GATA4, Twist1 and EndMT effector gene (Snail, Slug and N cadherin) expression at the inner curvature (lower WSS) compared to the outer curvature (higher WSS) of porcine and murine aortae (all p < 0.05). Snail expression at the inner curvature of the murine aorta was reduced by deletion of Twist1 in EC (Tie-2 Twist1KO) compared to controls (Twist1 fl/fl; p < 0.05), demonstrating that Twist1 promotes Snail expression at a low WSS site in vivo. To establish a causal link between flow and EndMT, WSS was modified in murine carotid arteries using a constrictive cuff, the study revealed elevated Twist1 expression at the low WSS site (proximal to stenosis) and enhanced GATA4 and Snail expression at the low, oscillatory WSS site (distal). Similarly, GATA4, Twist1 and EndMT effector genes (Snail, Slug and N cadherin) were induced in porcine aortic EC (PAEC) or human umbilical vein EC (HUVEC) exposed to low, oscillatory WSS for 72h using an orbital plate system (all p < 0.05). Gene silencing demonstrated that GATA4 and Twist1 are required for Snail induction in EC exposed to low, oscillatory WSS, and chromatin immunoprecipitation revealed GATA4 interaction with promoter regions of Twist1 and Snail. Low, oscillatory WSS promoted several changes that are characteristic of EndMT including N-cadherin induction, VE-cadherin disorganisation and enhanced proliferation (all p < 0.05). Silencing of GATA4, Twist1 and Snail significantly reduced these processes and limited EC permeability (all p < 0.05) in EC exposed to low, oscillatory WSS. Conclusions We conclude that low WSS induces EndMT and subsequent EC proliferation and permeability through the induction of GATA4 and Twist1. Our observations illuminate for the first time, the role of EndMT in arterial biomechanics and injury. Future studies should define the role of EndMT in focal atherosclerosis.


Heart | 2015

206 Using Magnetic Tweezers to probe Mechanically-Induced Signalling in Endothelial Cells

Matthew T. Bryan; Ioannis Xanthis; Sarah Hsiao; Paul C. Evans

Introduction Atherosclerosis is an inflammatory arterial disease that develops in regions exposed to disturbed flow, such as at bends. Blood flow affects endothelial cells through drag forces (shear stress) and by modifying biomolecular motion around the cell (mass transport). Flow systems commonly used in vitro to induce cellular signalling cannot distinguish between the shear stress and mass transport mechanisms and trigger multiple stress-sensitive receptors (mechanoreceptors) simultaneously. Magnetic tweezers are an alternative method, applying force directly to specific mechanoreceptors. Here, we describe the development of magnetic tweezers that can apply two-dimensional (2D) forces and demonstrate their potential for studying live-cell signalling processes. Methods and results A four-poled electromagnet was built as part of a magnetic tweezers platform. Each pole was independently powered, enabling the 2D magnetic field profile between the poles to be controlled. ANSYS software was used to computationally model the magnetic field profile produced in the region between the pole pieces and the maximum force calculated as 16 pN per bead. The electromagnet was embedded within a fluorescence microscope fitted with an incubation chamber heated to 37ºC, enabling live-cell imaging during force application. Computer control of the magnetic field profile enabled the generation of forces of arbitrary magnitude, direction and oscillation frequency. Human umbilical vein endothelial cells (HUVEC) were cultured in fibronectin-coated dishes until they reached confluency and were serum-starved prior to experimentation. Cells were loaded with a calcium-sensitive fluorescent dye prior to the application of superparamagnetic beads coated with antibodies that recognise integrin-β1. Cells were imaged for 3 min without force to define a signalling baseline, followed by 3 min of applied force. Force applied to the mechanoreceptors initiated calcium influx around the beads. Using single-cell analysis, the amplitudes of the calcium influx peaks were quantified. It was observed that peak amplitude significantly increased under constant 16 pN force and that the response under force was similar to that induced by 15 dyne/cm2 laminar flow (Figure 1). Abstract 206 Figure 1 Ca peak amplitudes under (a) 16 pN force and (b) 15 dyne/cm2 flow. Bars show mean ± SEM; unpaired two-tailed t-test (n = 4–13) Conclusions Magnetic tweezers were built around a fluorescence microscope to enable live-cell imaging of cell signalling during force application. Using calcium signalling to validate the approach, the feasibility of using the magnetic tweezers to induce a mechanoresponse was demonstrated. The flexible design of the magnetic tweezers means it has the potential to uncover the mechanisms through which shear stress is converted into a biological signal, since it can be adapted to study a variety of mechanoreceptors, signalling pathways and force profiles.

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Shuang Feng

University of Sheffield

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Ismael Gauci

University of Sheffield

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Julian Gunn

University of Sheffield

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Kim Van der Heiden

Erasmus University Rotterdam

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Neil Bowden

University of Sheffield

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Rosemary Kim

University of Sheffield

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