Prdm16 Supports Arterial Flow Recovery by Maintaining Endothelial Function.
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ABSTRACT:
SUBMITTER: Craps S
PROVIDER: S-EPMC8221541 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The arterial endothelium’s response to its flow environment is critical to vascular homeostasis. The endothelial glycocalyx has been shown to play a major role in mechanotransduction, but the extent to which the components of the glycocalyx affect the overall function of the endothelium remains unclear. The objective of this study was to further elucidate the role of heparan sulfate as a mechanosensor on the surface of the arterial endothelium, by (1) expanding the variety of shear waveforms investigated, (2) continuously suppressing heparan sulfate expression rather than using a pre-flow batch treatment, and (3) performing microarray analysis on post-flow samples. Porcine aortic endothelial cells were exposed to non-reversing, reversing, and oscillatory shear waveforms for 24 hours with or without continuous heparan sulfate suppression with heparinase. All shear waveforms significantly increased the amount of heparan sulfate on the surface of the endothelium. Suppression of heparan sulfate to less than 25% of control levels did not inhibit shear-induced cell alignment or nitric oxide production, or alter gene expression, for any of the shear waveforms investigated. We infer that heparan sulfate on the surface of porcine aortic endothelial cells is not the primary mechanosensor for many shear-responsive endothelial cell functions in this species. Porcine aortic endothelial cells were exposed to 3 different shear waveforms for 24 hours with or without the addition of 300 mU/ml heparinase III to the flow media. The shear waveforms inculded Non-reversing (15 ± 15 dyne/cm2, 1 Hz), Steady (15 dyne/cm2), or Oscillatory (0 ± 15 dyne/cm2, 1 Hz) shear. Four replicates of each condition were performed for a total of 24 experiments. Each experimental sample was hybridized to an oligonucleotide array along with a standard reference sample (static cells).
2011-07-21 | E-GEOD-30843 | biostudies-arrayexpress
Project description:The arterial endothelium’s response to its flow environment is critical to vascular homeostasis. The endothelial glycocalyx has been shown to play a major role in mechanotransduction, but the extent to which the components of the glycocalyx affect the overall function of the endothelium remains unclear. The objective of this study was to further elucidate the role of heparan sulfate as a mechanosensor on the surface of the arterial endothelium, by (1) expanding the variety of shear waveforms investigated, (2) continuously suppressing heparan sulfate expression rather than using a pre-flow batch treatment, and (3) performing microarray analysis on post-flow samples. Porcine aortic endothelial cells were exposed to non-reversing, reversing, and oscillatory shear waveforms for 24 hours with or without continuous heparan sulfate suppression with heparinase. All shear waveforms significantly increased the amount of heparan sulfate on the surface of the endothelium. Suppression of heparan sulfate to less than 25% of control levels did not inhibit shear-induced cell alignment or nitric oxide production, or alter gene expression, for any of the shear waveforms investigated. We infer that heparan sulfate on the surface of porcine aortic endothelial cells is not the primary mechanosensor for many shear-responsive endothelial cell functions in this species.
2011-07-22 | GSE30843 | GEO
Project description:Atherosclerotic plaque preferentially develops in arterial curvatures and branching regions, where endothelial cells constantly experience disturbed blood flow. By contrast, the straight arteries are generally protected from plaque formation due to exposure of endothelial cells to vaso-protective laminar blood flow. However, the role of flow patterns on endothelial barrier function remains largely unclear. This study aimed to investigate new mechanisms underlying the blood flow pattern-regulated endothelial integrity. Exposure of human endothelial cells to pulsatile shear (PS, mimicking the laminar flow) compared to oscillatory shear (OS, mimicking the disturbed flow) increased the expressions of long non-coding RNA MALAT1 and tight junction proteins ZO1 and Occludin. This increase was abolished by knocking down MALAT1 or Nesprin1 and 2. PS promoted the association between Nesprin1 and SUN2 at the nuclear envelopes, and induced a nuclear translocation of ?-catenin, likely through enhancing the interaction between ?-catenin and Nesprin1. In the in vivo study, mice were treated via intraperitoneal injection with ?-catenin agonist SKL2001 or its inhibitor XAV939, and they were then subjected to Evans blue injection to assess aortic endothelial permeability. The aortas exhibited a reduced wall permeability to Evans blue in SKL2001-treated mice whereas an enhanced permeability in XAV939-treated mice. We concluded that laminar flow promotes nuclear localization of Nesprins, which facilitates the nuclear access of ?-catenin to stimulate MALAT1 transcription, resulting in increased expressions of ZO1 and Occludin to protect endothelial barrier function.
| S-EPMC7330101 | biostudies-literature
Project description:OBJECTIVES:To determine whether patients with treated depression but no other risk factors for coronary heart disease (CHD) have abnormal arterial endothelial function, an abnormality that is common to other acquired risk factors for CHD. DESIGN:Case-control study. SETTING:Secondary care departments of cardiology and psychiatry in a single centre and the surrounding community. PARTICIPANTS:Patients with treated depression and matched healthy controls, aged 18-55 years, without conventional acquired risk factors for CHD. These were recruited from local community mental health clinics, general practices, and patient support groups, and through posters placed in public areas of the hospital. Patients had major depression as defined in the American Psychiatric Association's Diagnostic and statistical manual of mental disorders, fourth edition. Fifteen patients and 12 controls were recruited, and 12 patients and 10 controls completed the study. OUTCOMES:Brachial artery flow mediated dilatation and baroreflex sensitivity. RESULTS:Arterial endothelial function measured by flow mediated dilatation was impaired in depression (mean (SEM) -0.7% (1.7%)) compared with controls (5.7% (0.9%), p = 0.005 by non-paired t test). Baroreflex sensitivity did not differ significantly between the groups. CONCLUSION:Arterial endothelial function is impaired in treated depression. This abnormality may contribute to the increased risk of CHD seen in depression.
| S-EPMC1767404 | biostudies-literature
Project description:Blood flow plays crucial roles in vascular development, remodeling and homeostasis, but the molecular pathways required for transducing flow signals are not well understood. In zebrafish embryos, arterial expression of activin receptor-like kinase 1 (alk1), which encodes a TGF? family type I receptor, is dependent on blood flow, and loss of alk1 mimics lack of blood flow in terms of dysregulation of a subset of flow-responsive arterial genes and increased arterial endothelial cell number. These data suggest that blood flow activates Alk1 signaling to promote a flow-responsive gene expression program that limits nascent arterial caliber. Here, we demonstrate that restoration of endothelial alk1 expression to flow-deprived arteries fails to rescue Alk1 activity or normalize arterial endothelial cell gene expression or number, implying that blood flow may play an additional role in Alk1 signaling independent of alk1 induction. To this end, we define cardiac-derived Bmp10 as the crucial ligand for endothelial Alk1 in embryonic vascular development, and provide evidence that circulating Bmp10 acts through endothelial Alk1 to limit endothelial cell number in and thereby stabilize the caliber of nascent arteries. Thus, blood flow promotes Alk1 activity by concomitantly inducing alk1 expression and distributing Bmp10, thereby reinforcing this signaling pathway, which functions to limit arterial caliber at the onset of flow. Because mutations in ALK1 cause arteriovenous malformations (AVMs), our findings suggest that an impaired flow response initiates AVM development.
| S-EPMC3737721 | biostudies-literature
Project description:BackgroundIt is uncertain whether saturated fatty acids (SFAs) impair endothelial function and contribute to arterial stiffening.ObjectiveWe tested the effects of replacing SFAs with monounsaturated fatty acids (MUFAs) or carbohydrates on endothelial function and arterial stiffness.DesignWith the use of a parallel-designed randomized controlled trial in 121 insulin-resistant men and women, we measured vascular function after 1 mo of consumption of a high-SFA (HS) diet and after 24 wk after random assignment to the HS diet or diets that contained <10% SFAs and were high in either MUFAs or carbohydrates. The primary outcome was a change in flow-mediated dilation (FMD), and secondary outcomes were changes in carotid to femoral pulse wave velocity (PWV) and plasma 8-isoprostane F2?-III concentrations.ResultsFor 112 participants with data available for analysis on the specified outcomes, no significant differences were shown. FMD with the HS reference diet was 6.7 ± 2.2%, and changes (95% CIs) after 6 mo of intervention were +0.3 (-0.4, 1.1), -0.2 (-0.8, 0.5), and -0.1 (-0.6, 0.7) with HS, high-MUFA (HM), and high-carbohydrate (HC) diets, respectively. After consumption of the HS reference diet, the geometric mean (±SD) PWV was 7.67 ± 1.62 m/s, and mean percentages of changes (95% CIs) were -1.0 (-6.2, 4.3) with the HS diet, 2.7 (-1.4, 6.9) with the HM diet, and -1.0 (-5.5, 3.4) with the HC diet. With the HS reference diet, the geometric mean (±SD) plasma 8-isoprostane F2?-III concentration was 176 ± 85 pmol/L, and mean percentage of changes (95% CIs) were 1 (-12, 14) with the HS diet, 6 (-5, 16) with the HM diet, and 4 (-7, 16) with the HC diet.ConclusionThe replacement of SFAs with MUFAs or carbohydrates in healthy subjects does not affect vascular function. This trial was registered at Current Controlled Trials (http://www.controlled-trials.com/ISRCTN) as ISRCTN 29111298.
| S-EPMC3743730 | biostudies-literature
Project description:BackgroundUnilateral ischemic stroke disrupts the well balanced interactions within bilateral cortical networks. Restitution of interhemispheric balance is thought to contribute to post-stroke recovery. Longitudinal measurements of cerebral blood flow (CBF) changes might act as surrogate marker for this process.ObjectiveTo quantify longitudinal CBF changes using arterial spin labeling MRI (ASL) and interhemispheric balance within the cortical sensorimotor network and to assess their relationship with motor hand function recovery.MethodsLongitudinal CBF data were acquired in 23 patients at 3 and 9 months after cortical sensorimotor stroke and in 20 healthy controls using pulsed ASL. Recovery of grip force and manual dexterity was assessed with tasks requiring power and precision grips. Voxel-based analysis was performed to identify areas of significant CBF change. Region-of-interest analyses were used to quantify the interhemispheric balance across nodes of the cortical sensorimotor network.ResultsDexterity was more affected, and recovered at a slower pace than grip force. In patients with successful recovery of dexterous hand function, CBF decreased over time in the contralesional supplementary motor area, paralimbic anterior cingulate cortex and superior precuneus, and interhemispheric balance returned to healthy control levels. In contrast, patients with poor recovery presented with sustained hypoperfusion in the sensorimotor cortices encompassing the ischemic tissue, and CBF remained lateralized to the contralesional hemisphere.ConclusionsSustained perfusion imbalance within the cortical sensorimotor network, as measured with task-unrelated ASL, is associated with poor recovery of dexterous hand function after stroke. CBF at rest might be used to monitor recovery and gain prognostic information.
| S-EPMC4156327 | biostudies-literature
Project description:Atherosclerosis is a heterogeneously distributed disease of arteries in which the endothelium plays an important central role. Spatial transcriptome profiling of endothelium in pre-lesional arteries has demonstrated differential phenotypes primed for athero-susceptibility at hemodynamic sites associated with disturbed blood flow. DNA methylation is a powerful epigenetic regulator of endothelial transcription recently associated with flow characteristics. We investigated differential DNA methylation in flow region-specific aortic endothelial cells in vivo in adult domestic male and female swine.Genome-wide DNA methylation was profiled in endothelial cells (EC) isolated from two robust locations of differing patho-susceptibility:--an athero-susceptible site located at the inner curvature of the aortic arch (AA) and an athero-protected region in the descending thoracic (DT) aorta. Complete methylated DNA immunoprecipitation sequencing (MeDIP-seq) identified over 5500 endothelial differentially methylated regions (DMRs). DMR density was significantly enriched in exons and 5'UTR sequences of annotated genes, 60 of which are linked to cardiovascular disease. The set of DMR-associated genes was enriched in transcriptional regulation, pattern specification HOX loci, oxidative stress and the ER stress adaptive pathway, all categories linked to athero-susceptible endothelium. Examination of the relationship between DMR and mRNA in HOXA genes demonstrated a significant inverse relationship between CpG island promoter methylation and gene expression. Methylation-specific PCR (MSP) confirmed differential CpG methylation of HOXA genes, the ER stress gene ATF4, inflammatory regulator microRNA-10a and ARHGAP25 that encodes a negative regulator of Rho GTPases involved in cytoskeleton remodeling. Gender-specific DMRs associated with ciliogenesis that may be linked to defects in cilia development were also identified in AA DMRs.An endothelial methylome analysis identifies epigenetic DMR characteristics associated with transcriptional regulation in regions of atherosusceptibility in swine aorta in vivo. The data represent the first methylome blueprint for spatio-temporal analyses of lesion susceptibility predisposing to endothelial dysfunction in complex flow environments in vivo.
| S-EPMC4492093 | biostudies-literature
Project description:Little is known about the role of endothelial progenitor cells (EPCs) in atherosclerosis. Accordingly, we performed a series of assessments with hypercholesterolemic (apolipoprotein E-null [ApoE(-/-)]) and wild-type (WT) mice to evaluate how cholesterol influences reendothelialization, atherosclerosis, and EPC function after arterial injury.Unexpectedly, reendothelialization (assessed by resistance to Evans blue staining) and circulating EPC counts (EPC culture assay) were greater in ApoE(-/-) mice than in WT mice, and transplantation of ApoE(-/-) bone marrow in WT mice accelerated endothelial recovery and increased recruitment of bone marrow-derived EPCs to the neoendothelium. Cholesterol concentration-dependently promoted the proliferation (MTS assay) of both ApoE(-/-) and WT EPCs, and the concentration dependence of EPC adhesion (to vitronectin-, collagen type I-, fibronectin-, and laminin-coated plates), migration (modified Boyden chamber assay), and antiapoptotic (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling stain) activity was biphasic. Cholesterol enhanced the messenger RNA expression (quantitative, real-time reverse-transcription polymerase chain reaction) of vascular endothelial growth factor and inhibited Notch1 messenger RNA expression in both ApoE(-/-) and WT EPCs, whereas endothelial nitric oxide synthase messenger RNA expression increased in ApoE(-/-) EPCs and declined in WT EPCs after cholesterol exposure. EPC activity was greater in Notch1(+/-) EPCs than in WT EPCs, and transplantation of Notch1(+/-) bone marrow accelerated endothelial recovery after arterial injury in WT mice.The results presented here provide novel insights into the role of EPCs during atherosclerosis and suggest that cholesterol and Notch1 may be involved in the regulation of EPC activity.
| S-EPMC2838724 | biostudies-literature
Project description:BackgroundElevated cardiovascular disease risk is observed in patients with COPD. Non-invasive assessments of endothelial dysfunction and arterial stiffness have recently emerged to provide mechanistic insight into cardiovascular disease risk in COPD; however, the reproducibility of endothelial function and arterial stiffness has yet to be investigated in this patient population.ObjectivesThis study sought to examine the within-day and between-day reproducibility of endothelial function and arterial stiffness in patients with COPD.MethodsBaseline diameter, peak diameter, flow-mediated dilation, augmentation index, augmentation index at 75 beats per minute, and pulse wave velocity were assessed three times in 17 patients with COPD (six males, eleven females, age range 47-75 years old; forced expiratory volume in 1 second =51.5% predicted). Session A and B were separated by 3 hours (within-day), whereas session C was conducted at least 7 days following session B (between-day). Reproducibility was assessed by: 1) paired t-tests, 2) coefficients of variation, 3) coefficients of variation prime, 4) intra-class correlation coefficient, 5) Pearson's correlations (r), and 6) Bland-Altman plots. Five acceptable assessments were required to confirm reproducibility.ResultsSix out of six within-day criteria were met for endothelial function and arterial stiffness outcomes. Six out of six between-day criteria were met for baseline and peak diameter, augmentation index and pulse wave velocity, whereas five out of six criteria were met for flow-mediated dilation.ConclusionThe present study provides evidence for within-day and between-day reproducibility of endothelial function and arterial stiffness in patients with COPD.
| S-EPMC4577266 | biostudies-literature