scholarly journals High Glucose Activates YAP Signaling to Promote Vascular Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Jeremy Ortillon ◽  
Jean-Christophe Le Bail ◽  
Elise Villard ◽  
Bertrand Léger ◽  
Bruno Poirier ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
High Glucose ◽  
Oscillatory Flow ◽  
Vascular Inflammation ◽  
Vascular Complications ◽  
Diabetic Mice ◽  
Flow Conditions ◽  
Endothelial Inflammation

Background and AimsThe YAP/TAZ signaling is known to regulate endothelial activation and vascular inflammation in response to shear stress. Moreover, YAP/TAZ signaling plays a role in the progression of cancers and renal damage associated with diabetes. However, whether YAP/TAZ signaling is also implicated in diabetes-associated vascular complications is not known.MethodsThe effect of high glucose on YAP/TAZ signaling was firstly evaluated in vitro on endothelial cells cultured under static conditions or subjected to shear stress (either laminar or oscillatory flow). The impact of diabetes on YAP/TAZ signaling was additionally assessed in vivo in db/db mice.ResultsIn vitro, we found that YAP was dephosphorylated/activated by high glucose in endothelial cells, thus leading to increased endothelial inflammation and monocyte attachment. Moreover, YAP was further activated when high glucose was combined to laminar flow conditions. YAP was also activated by oscillatory flow conditions but, in contrast, high glucose did not exert any additional effect. Interestingly, inhibition of YAP reduced endothelial inflammation and monocyte attachment. Finally, we found that YAP is also activated in the vascular wall of diabetic mice, where inflammatory markers are also increased.ConclusionWith the current study we demonstrated that YAP signaling is activated by high glucose in endothelial cells in vitro and in the vasculature of diabetic mice, and we pinpointed YAP as a regulator of high glucose-mediated endothelial inflammation and monocyte attachment. YAP inhibition may represent a potential therapeutic opportunity to improve diabetes-associated vascular complications.

Abstract 445: Endothelial Inflammation and Loss of Bone Morphogenetic Protein Receptor 2 in Oscillatory Shear Stress Model

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Collins Ezeuka
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Laminar Flow ◽  
Bone Morphogenetic Protein ◽  
Aortic Endothelial Cells ◽  
Bone Morphogenetic Protein Receptor ◽  
Endothelial Inflammation ◽  
Protein Receptor ◽  
Morphogenetic Protein

Background: Bone Morphogenetic Protein Receptor II (BMPR2) plays an unexpected role as a critical anti-inflammatory and anti-atherogenic protein in endothelial cells (ECs) via a reactive oxygen species (ROS) and NFκB-dependent mechanism. Pro-atherogenic stimuli such as disturbed laminar flow, angiotensin II, hypercholesterolemia and the pro-inflammatory cytokine TNFα, significantly downregulate BMPR2 expression in endothelium, while anti-atherogenic stimuli such as laminar flow and statins upregulate BMPR2’s expression in vivo and in vitro. These findings suggest that there may be a common mechanism by which pro-atherogenic factors downregulate BMPR2 expression and that protecting or restoring its expression could be a novel therapeutic approach for prevention and treatment of atherosclerosis. Our preliminary studies have identified microRNAs that possibly play a causative role in the loss of BMPR2, by binding to its 3’-UTR, leading to degradation of BMPR2, endothelial dysfunction, inflammation, and subsequent atherosclerosis. Hypothesis: Rescuing loss of BMPR2 will decrease endothelial inflammation and atherosclerosis Methods: Our in vitro model of disturbed blood flow is characterized by a cone and plate system, wherein mouse aortic endothelial cells are subjected to unidirectional laminar shear (LS 15 dyn/cm2) or oscillatory shear (OS, +/1 5 dyn/cm2 at 1 Hz frequency) for 24 hours. Endothelial cell inflammatory markers, BMPR2, and specific microRNA mRNA transcript fold changes, were then assessed via qPCR. Results: Under oscillatory flow conditions, in our in vitro shear stress system, BMPR2 is lost and mouse aortic endothelial cells acquire an inflammation phenotype, with a corresponding increase in the fold change of mRNA for microRNAs-17, 21, 25, and 181. Conclusion: We have identified microRNAs that may target BMPR2, leading to its degradation, and subsequent onset of endothelial inflammation. Blocking the aforementioned microRNAs may represent a novel therapy in the treatment of endothelial inflammation and subsequent atherosclerosis.

scholarly journals Potential Effect of Polyphenolic-Rich Fractions of Corn Silk on Protecting Endothelial Cells against High Glucose Damage Using In Vitro and In Vivo Approaches

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3665
Author(s):  
Nurraihana Hamzah ◽  
Sabreena Safuan ◽  
Wan Rosli Wan Ishak
Keyword(s):  
Endothelial Cells ◽  
Protective Effect ◽  
High Glucose ◽  
Vascular Complications ◽  
Diabetic Rats ◽  
Diabetic Patients ◽  
Dependent Manner ◽  
Corn Silk

Endothelial cell dysfunction is considered to be one of the major causes of vascular complications in diabetes. Polyphenols are known as potent antioxidants that can contribute to the prevention of diabetes. Corn silk has been reported to contain polyphenols and has been used in folk medicine in China for the treatment of diabetes. The present study aims to investigate the potential protective role of the phenolic-rich fraction of corn silk (PRF) against injuries to vascular endothelial cells under high glucose conditions in vitro and in vivo. The protective effect of PRF from high glucose toxicity was investigated using human umbilical vein endothelial cells (HUVECs). The protective effect of PRF was subsequently evaluated by using in vivo methods in streptozotocin (STZ)-induced diabetic rats. Results showed that the PRF significantly reduced the cytotoxicity of glucose by restoring cell viability in a dose-dependent manner. PRF was also able to prevent the histological changes in the aorta of STZ-induced diabetic rats. Results suggested that PRF might have a beneficial effect on diabetic patients and may help to prevent the development and progression of diabetic complications such as diabetic nephropathy and atherosclerosis.

scholarly journals Platelet-derived calpain cleaves the endothelial protease-activated receptor 1 to induce vascular inflammation in diabetes

2020 ◽  
Vol 115 (6) ◽  
Author(s):  
Anastasia Kyselova ◽  
Amro Elgheznawy ◽  
Ilka Wittig ◽  
Juliana Heidler ◽  
Alexander W. Mann ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Inflammation ◽  
Vascular Complications ◽  
Cysteine Proteases ◽  
Calpain Inhibitor ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Endothelial Protein C Receptor ◽  
Tnf Α ◽  
Protease Activated Receptor 1

AbstractDiabetes mellitus is a major risk factor for cardiovascular disease. Platelets from diabetic patients are hyperreactive and release microparticles that carry activated cysteine proteases or calpains. Whether platelet-derived calpains contribute to the development of vascular complications in diabetes is unknown. Here we report that platelet-derived calpain1 (CAPN1) cleaves the protease-activated receptor 1 (PAR-1) on the surface of endothelial cells, which then initiates a signaling cascade that includes the activation of the tumor necrosis factor (TNF)-α converting enzyme (TACE). The latter elicits the shedding of the endothelial protein C receptor and the generation of TNF-α, which in turn, induces intracellular adhesion molecule (ICAM)-1 expression to promote monocyte adhesion. All of the effects of CAPN1 were mimicked by platelet-derived microparticles from diabetic patients or from wild-type mice but not from CAPN1−/− mice, and were not observed in PAR-1-deficient endothelial cells. Importantly, aortae from diabetic mice expressed less PAR-1 but more ICAM-1 than non-diabetic mice, effects that were prevented by treating diabetic mice with a calpain inhibitor as well as by the platelet specific deletion of CAPN1. Thus, platelet-derived CAPN1 contributes to the initiation of the sterile vascular inflammation associated with diabetes via the cleavage of PAR-1 and the release of TNF-α from the endothelial cell surface.

scholarly journals High Glucose and Hypoxia-Mediated Damage to Human Brain Microvessel Endothelial Cells Induces an Altered, Pro-Inflammatory Phenotype in BV-2 Microglia In Vitro

2020 ◽  
Author(s):  
Jaclyn Iannucci ◽  
Haripriya Vittal Rao ◽  
Paula Grammas
Keyword(s):  
Endothelial Cells ◽  
Human Brain ◽  
High Glucose ◽  
Vascular Inflammation ◽  
Brain Endothelial Cells ◽  
Cerebral Microcirculation ◽  
Microglial Phagocytosis ◽  
Brain Microvessel ◽  
Factor Α

Abstract Diabetes is strongly linked to the development of Alzheimer’s disease (AD), though the mechanisms for this enhanced risk are unclear. Because vascular inflammation is a consistent feature of both diabetes and AD, the cerebral microcirculation could be a key target for the effects of diabetes in the brain. The goal of this study is to explore whether brain endothelial cells, injured by diabetes-related insults, glucose and hypoxia, can affect inflammatory and activation processes in microglia in vitro. Human brain microvascular endothelial cells (HBMVECs) were either treated with 5 mM glucose (control), 30 mM glucose (high glucose), exposed to hypoxia, or exposed to hypoxia plus high glucose. HBMVEC-conditioned medium was then used to treat BV-2 microglia. Alterations in microglia phenotype were assessed through measurement of nitric oxide (NO), cytokine production, microglial activation state markers, and microglial phagocytosis. HBMVECs were injured by exposure to glucose and/or hypoxia, as assessed by release of LDH, interleukin (IL)-1β, and reactive oxygen species (ROS). HBMVECs injured by glucose and hypoxia induced increases in microglial production of NO, tumor necrosis factor-α (TNFα) and matrix metalloproteinase (MMP)-9. Injured HBMVECs significantly increased microglial expression of CD11c and CLEC7A, and decreased expression of the homeostatic marker P2RY12. Finally, bead uptake by BV-2 cells, an index of phagocytic ability, was elevated by conditioned media from injured HBMVECs. The demonstration that injury to brain endothelial cells by diabetic-associated insults, glucose and hypoxia, promotes microglial inflammation supports the idea that the cerebral microcirculation is a critical locus for the deleterious effects of diabetes in the AD brain.

scholarly journals Crocodile blood supplementation protects vascular function in diabetic mice

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Chui Yiu Bamboo Chook ◽  
Francis M. Chen ◽  
Gary Tse ◽  
Fung Ping Leung ◽  
Wing Tak Wong
Keyword(s):  
Endothelial Cells ◽  
Vascular Function ◽  
Quantitative Polymerase Chain Reaction ◽  
Functional Study ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Gene Expressions ◽  
Inflammatory State ◽  
Crocodile Blood

Abstract Cardiovascular disease is a major cause of mortality in diabetic patients due to the heightened oxidative stress and pro-inflammatory state in vascular tissues. Effective approaches targeting cardiovascular health for diabetic patients are urgently needed. Crocodile blood, an emerging dietary supplement, was suggested to have anti-oxidative and anti-inflammatory effects in vitro, which have yet to be proven in animal models. This study thereby aimed to evaluate whether crocodile blood can protect vascular function in diabetic mice against oxidation and inflammation. Diabetic db/db mice and their counterparts db/m+ mice were treated daily with crocodile blood soluble fraction (CBSF) or vehicle via oral gavage for 4 weeks before their aortae were harvested for endothelium-dependent relaxation (EDR) quantification using wire myograph, which is a well-established functional study for vascular function indication. Organ culture experiments culturing mouse aortae from C57BL/6 J mice with or without IL-1β and CBSF were done to evaluate the direct effect of CBSF on endothelial function. Reactive oxygen species (ROS) levels in mouse aortae were assessed by dihydroethidium (DHE) staining with inflammatory markers in endothelial cells quantified by quantitative polymerase chain reaction (qPCR). CBSF significantly improved deteriorated EDR in db/db diabetic mice through both diet supplementation and direct culture, with suppression of ROS level in mouse aortae. CBSF also maintained EDR and reduced ROS levels in mouse aortae against the presence of pro-inflammatory IL-1β. Under the pro-inflammatory state induced by IL-1β, gene expressions of inflammatory cytokines were downregulated, while the protective transcripts UCP2 and SIRT6 were upregulated in endothelial cells. Our study suggests a novel beneficial effect of crocodile blood on vascular function in diabetic mice and that supplementation of diet with crocodile blood may act as a complementary approach to protect against vascular diseases through anti-oxidation and anti-inflammation in diabetic patients. Graphical abstract

scholarly journals Investigation of Wall Shear Stress in Cardiovascular Research and in Clinical Practice—From Bench to Bedside

2021 ◽  
Vol 22 (11) ◽  
pp. 5635
Author(s):  
Katharina Urschel ◽  
Miyuki Tauchi ◽  
Stephan Achenbach ◽  
Barbara Dietel
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Wall Shear Stress ◽  
Cell Function ◽  
Computational Techniques ◽  
Apical Surface ◽  
Cardiovascular Research ◽  
Endothelial Cell Function ◽  
Wall Shear

In the 1900s, researchers established animal models experimentally to induce atherosclerosis by feeding them with a cholesterol-rich diet. It is now accepted that high circulating cholesterol is one of the main causes of atherosclerosis; however, plaque localization cannot be explained solely by hyperlipidemia. A tremendous amount of studies has demonstrated that hemodynamic forces modify endothelial athero-susceptibility phenotypes. Endothelial cells possess mechanosensors on the apical surface to detect a blood stream-induced force on the vessel wall, known as “wall shear stress (WSS)”, and induce cellular and molecular responses. Investigations to elucidate the mechanisms of this process are on-going: on the one hand, hemodynamics in complex vessel systems have been described in detail, owing to the recent progress in imaging and computational techniques. On the other hand, investigations using unique in vitro chamber systems with various flow applications have enhanced the understanding of WSS-induced changes in endothelial cell function and the involvement of the glycocalyx, the apical surface layer of endothelial cells, in this process. In the clinical setting, attempts have been made to measure WSS and/or glycocalyx degradation non-invasively, for the purpose of their diagnostic utilization. An increasing body of evidence shows that WSS, as well as serum glycocalyx components, can serve as a predicting factor for atherosclerosis development and, most importantly, for the rupture of plaques in patients with high risk of coronary heart disease.

Focal TLR4 activation mediates disturbed flow-induced endothelial inflammation

2019 ◽  
Vol 116 (1) ◽  
pp. 226-236 ◽  
Author(s):  
Dan Qu ◽  
Li Wang ◽  
Mingyu Huo ◽  
Wencong Song ◽  
Chi-Wai Lau ◽  
...  
Keyword(s):  
Vascular Inflammation ◽  
Subsequent Development ◽  
Tlr4 Expression ◽  
Disturbed Flow ◽  
Atherosclerotic Lesions ◽  
Endothelial Inflammation ◽  
En Face ◽  
Induced Flow ◽  
Tlr4 Activation

Abstract Aims Disturbed blood flow at arterial branches and curvatures modulates endothelial function and predisposes the region to endothelial inflammation and subsequent development of atherosclerotic lesions. Activation of the endothelial Toll-like receptors (TLRs), in particular TLR4, contributes to vascular inflammation. Therefore, we investigate whether TLR4 can sense disturbed flow (DF) to mediate the subsequent endothelial inflammation. Methods and results En face staining of endothelium revealed that TLR4 expression, activation, and its downstream inflammatory markers were elevated in mouse aortic arch compared with thoracic aorta, which were absent in Tlr4mut mice. Similar results were observed in the partial carotid ligation model where TLR4 signalling was activated in response to ligation-induced flow disturbance in mouse carotid arteries, and such effect was attenuated in Tlr4mut mice. DF in vitro increased TLR4 expression and activation in human endothelial cells (ECs) and promoted monocyte-EC adhesion, which were inhibited in TLR4-knockdown ECs. Among endogenous TLR4 ligands examined as candidate mediators of DF-induced TLR4 activation, fibronectin containing the extra domain A (FN-EDA) expressed by ECs was increased by DF and was revealed to directly interact with and activate TLR4. Conclusion Our findings demonstrate the indispensable role of TLR4 in DF-induced endothelial inflammation and pinpoint FN-EDA as the endogenous TLR4 activator in this scenario. This novel mechanism of vascular inflammation under DF condition may serve as a critical initiating step in atherogenesis.

Fisetin inhibits high-glucose-induced vascular inflammation in vitro and in vivo

2014 ◽  
Vol 63 (9) ◽  
pp. 779-787 ◽  
Author(s):  
Soyoung Kwak ◽  
Sae-Kwang Ku ◽  
Jong-Sup Bae
Keyword(s):  
High Glucose ◽  
Vascular Inflammation

scholarly journals Diverse functional responses to high glucose by primary and permanent hybrid endothelial cells in vitro

2021 ◽  
Author(s):  
Paweł Uruski ◽  
Justyna Mikuła-Pietrasik ◽  
Marcin Drzewiecki ◽  
Sylwia Budkiewicz ◽  
Marcin Gładki ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
High Glucose ◽  
Functional Responses
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