Effect of heparan sulfate cleavage on homeostatic gene expression in microvascular endothelial cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE260628 | GEO | 2024/08/14
REPOSITORIES: GEO
Similar Datasets
Project description:Objective: Considerable evidence links dietary salt intake with the development of hypertension, left ventricular hypertrophy, and increased risk of stroke and coronary heart disease. Despite extensive epidemiological and basic science interrogation of the relationship between high salt (HS) intake and blood pressure, it remains unclear how HS impacts endothelial cell (EC) and vascular structure in vivo. This study aims to uncover the HS-induced vascular pathologies using a differential systemic decellularization in vivo (DISDIVO) approach.Approach and Results: We performed systematic molecular characterization of the endothelial glycocalyx (eGC) and EC proteomes in mice with HS (8%) diet-induced hypertension versus healthy control animals. Isolation of eGC and ECs compartments was achieved using the DISDIVO approach. Altered protein expression in hypertensive compared to normal mice was characterized by liquid chromatography tandem-mass spectrometry (LC-MS/MS). Proteomic results from eGC fractions revealed a significant downregulation of eGC and associated proteins in HS diet-induced hypertensive mice. Among 1696 proteins identified in this group, 723 were markedly downregulated while 168 were upregulated, bioinformatic analysis indicates critical damage and derangement of eGC layer. In the ECs fraction HS-induced hypertension significantly altered protein mediators of contractility, metabolism, mechanotransduction, renal functions, and coagulation cascades. In particular, we observed dysregulation of integrin subunits alpha2, alpha2b, and alpha5, which relay external signals to the actin cytoskeleton.Conclusion: These findings provide novel molecular insight on HS-induced structure changes in eGC and ECs that may increase cardiovascular risk and potentially guide the development of new diagnostics and therapeutic interventions.
2023-10-24 | PXD031228 | Pride
Project description:Human induced pluripotent stem cells (hiPSCs) are used to study organogenesis and model disease as well as being developed for regenerative medicine. Endothelial cells are among the many cell types differentiated from hiPSC, but their maturation and stabilization fall short of that in adult endothelium. We examined whether shear stress alone or in combination with pericyte co-culture would induce flow alignment and maturation of hiPSC-derived endothelial cells (hiPSC-ECs) but found no effects comparable to those in primary microvascular EC. In addition, hiPSC-ECs lacked a luminal glycocalyx, critical for vasculature homeostasis, shear stress sensing and signalling. We noted however, that hiPSC-EC have dysfunctional mitochondrial permeability transition pores, resulting in reduced mitochondrial function and increased reactive oxygen species (ROS). Closure of these pores by cyclosporine-A improved EC mitochondrial function but also restored the glycocalyx such that alignment to flow took place. These indicated that mitochondrial maturation is required for proper hiPSC-EC functionality.
2019-12-14 | E-MTAB-8392 | biostudies-arrayexpress
Project description:Infiltration of peripheral immune cells after blood-brain barrier (BBB) dysfunction causes severe inflammation after a stroke. Although the endothelial glycocalyx functions as a barrier to circulating cells, the relationship between stroke severity and glycocalyx dysfunction remains unclear. In this study, glycosaminoglycans (GAGs), a component of the endothelial glycocalyx, in ischemic stroke were studied using a photochemically induced thrombosis (PIT) mouse model. As results, decreased levels of heparan sulfate (HS) and chondroitin sulfate (CS) and increased activity of hyaluronidase 1 and heparanase (HPSE) were observed in ischemic brain tissues. HPSE expression in cerebral vessels increased after stroke onset and infarct volume greatly decreased after co-administration of N-acetylcysteine (NAC)+GAG oligosaccharides as compared to NAC administration alone. These results suggest that the endothelial glycocalyx was injured after the onset of stroke. Interestingly, scission activity of proHPSE produced by HBMEC/ciβ and HEK293 cells transfected with hHPSE1 cDNA were activated by acrolein exposure. We identified the ACR modified amino acid residues of proHPSE using nano LC-MS/MS, suggesting that ACR modification of Lys139 (6-kDa linker), and Lys107 and Lys161, located in the immediate vicinity of the 6-kDa linker, at least in part, is attributed to the activation of proHPSE. Since proHPSE, but not HPSE, localizes outside cells by binding with HS proteoglycans, ACR-modified proHPSE represents a promising target to protect the endothelial glycocalyx.
2020-11-16 | PXD021040 | Pride
Project description:Giantsos-Adams2013 - Growth of glycocalyx
under static conditions
This model is described in the article:
Heparan Sulfate Regrowth
Profiles Under Laminar Shear Flow Following Enzymatic
Degradation.
Giantsos-Adams KM, Koo AJ, Song S,
Sakai J, Sankaran J, Shin JH, Garcia-Cardena G, Dewey CF.
Cell Mol Bioeng 2013 Jun; 6(2):
160-174
Abstract:
The local hemodynamic shear stress waveforms present in an
artery dictate the endothelial cell phenotype. The observed
decrease of the apical glycocalyx layer on the endothelium in
atheroprone regions of the circulation suggests that the
glycocalyx may have a central role in determining
atherosclerotic plaque formation. However, the kinetics for the
cells' ability to adapt its glycocalyx to the environment have
not been quantitatively resolved. Here we report that the
heparan sulfate component of the glycocalyx of HUVECs increases
by 1.4-fold following the onset of high shear stress, compared
to static cultured cells, with a time constant of 19 h.
Cell morphology experiments show that 12 h are required
for the cells to elongate, but only after 36 h have the
cells reached maximal alignment to the flow vector. Our
findings demonstrate that following enzymatic degradation,
heparan sulfate is restored to the cell surface within
12 h under flow whereas the time required is 20 h
under static conditions. We also propose a model describing the
contribution of endocytosis and exocytosis to apical heparan
sulfate expression. The change in HS regrowth kinetics from
static to high-shear EC phenotype implies a differential in the
rate of endocytic and exocytic membrane turnover.
This model is hosted on
BioModels Database
and identified by:
MODEL1609100001.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000830 | BioModels
Project description:Giantsos-Adams2013 - Growth of glycocalyx
under static conditions
This model is described in the article:
Heparan Sulfate Regrowth
Profiles Under Laminar Shear Flow Following Enzymatic
Degradation.
Giantsos-Adams KM, Koo AJ, Song S,
Sakai J, Sankaran J, Shin JH, Garcia-Cardena G, Dewey CF.
Cell Mol Bioeng 2013 Jun; 6(2):
160-174
Abstract:
The local hemodynamic shear stress waveforms present in an
artery dictate the endothelial cell phenotype. The observed
decrease of the apical glycocalyx layer on the endothelium in
atheroprone regions of the circulation suggests that the
glycocalyx may have a central role in determining
atherosclerotic plaque formation. However, the kinetics for the
cells' ability to adapt its glycocalyx to the environment have
not been quantitatively resolved. Here we report that the
heparan sulfate component of the glycocalyx of HUVECs increases
by 1.4-fold following the onset of high shear stress, compared
to static cultured cells, with a time constant of 19 h.
Cell morphology experiments show that 12 h are required
for the cells to elongate, but only after 36 h have the
cells reached maximal alignment to the flow vector. Our
findings demonstrate that following enzymatic degradation,
heparan sulfate is restored to the cell surface within
12 h under flow whereas the time required is 20 h
under static conditions. We also propose a model describing the
contribution of endocytosis and exocytosis to apical heparan
sulfate expression. The change in HS regrowth kinetics from
static to high-shear EC phenotype implies a differential in the
rate of endocytic and exocytic membrane turnover.
This model is hosted on
BioModels Database
and identified by:
MODEL1609100001.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2016-09-28 | MODEL1609100001 | BioModels
Project description:Acute hemorrhage commonly leads to coagulopathy and organ dysfunction or failure. Recent evidence suggests that damage to the endothelial glycocalyx contributes to these adverse outcomes. The physiological events mediating acute glycocalyx shedding are undefined, however. Here, we show that succinate accumulation within endothelial cells drives glycocalyx degradation through a membrane reorganization-mediated mechanism. We investigated this mechanism in a cultured endothelial cell hypoxia-reoxygenation model, in a rat model of hemorrhage, and in trauma patient plasma samples. We found that succinate metabolism by succinate dehydrogenase mediates glycocalyx damage through lipid oxidation and phospholipase A2-mediated membrane reorganization (increasing lysophospholipids), promoting the interaction of MMP24 and MMP25 with glycocalyx constituents. In trauma patients, we found that succinate levels were associated with glycocalyx damage and the development of coagulopathy, and that interaction of MMP24 and syndecan-1 were elevated compared to healthy controls. This establishes a novel metabolic cascade mediating the endotheliopathy of traumatic hemorrhage.
2023-01-30 | ST002461 | MetabolomicsWorkbench
Project description:Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. AM plays critical roles in blood vessels, including regulation of vascular stability and permeability. To elucidate the autocrine / paracrine function of AM in endothelial cells in vivo. A conditional knockout of AM in endothelial cells (AM EC-KO) was used. The amount of vascularization the matrigel implants was lower in AM EC-KO mice indicating a defective angiogenesis. Moreover, ablation of AM in endothelial cells revealed increased vascular permeability in comparison with wildtype littermates. In addition, AM EC-KO lungs exhibited significantly less tumor growth than littermate WT mice using a syngeneic model of metastasis. Furthermore, following middle cerebral artery permanent occlusion, there was a significant infarct size decrease in animals lacking endothelial AM when compared to their wild type counterparts. AM is an important regulator of EC function, angiogenesis, tumorigenesis and brain response to ischemia. Studies of AM should bring novel approaches to the treatment of vascular diseases. Lung endothelial mRNA profiles of wild type (WT) and adrenomedullin endothelial cell conditional knockout (AM EC-KO) mice were generated by deep sequencing using Illumina GAIIx.
2016-08-14 | E-GEOD-84345 | biostudies-arrayexpress
Project description:Aims: Novel cancer therapies leading to increased survivorship of cancer patients have been negated by a concomitant rise in cancer therapies-related cardiovascular toxicities. Sunitinib, a first line multi receptor tyrosine kinase inhibitor (TKI), has been reported to cause vascular dysfunction although the initiating mechanisms contributing to this side effect remain unknown. Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in endothelial cells (ECs); however, their roles in cancer therapies-related vascular toxicities remain underexplored. Methods and Results: We performed lncRNA expression profiling to identify potential lncRNAs that are dysregulated in human induced pluripotent stem cells-derived ECs (iPSC-ECs) treated with sunitinib. We show that the lncRNA hyaluronan synthase 2 antisense 1 (HAS2-AS1) is significantly diminished in sunitinib-treated iPSC-ECs. Sunitinib was found to downregulate HAS2-AS1 by an epigenetic mechanism involving hypermethylation. Depletion of HAS2-AS1 recapitulated sunitinib-induced detrimental effects on iPSC-ECs, whereas CRISPR-mediated activation of HAS2-AS1 reversed sunitinib-induced dysfunction. We confirm that HAS2-AS1 stabilizes the expression of its sense gene HAS2 via an RNA/mRNA heteroduplex formation. Knockdown of HAS2-AS1 led to reduced synthesis of hyaluronic acid (HA) and upregulation of ADAMTS5, an enzyme involved in extracellular matrix degradation, resulting in disruption of the endothelial glycocalyx which is critical for ECs. In vivo, sunitinib-treated mice showed reduced coronary flow reserve, accompanied by a reduction in has2os and degradation of the endothelial glycocalyx. Finally, we identify that treatment with high molecular-weight HA can prevent the deleterious effects of sunitinib both in vitro and in vivo by preserving the endothelial glycocalyx. Conclusions: Our findings highlight the importance of lncRNA-mediated regulation of the endothelial glycocalyx as an important determinant of sunitinib-induced vascular toxicity and reveal potential novel therapeutic avenues to attenuate sunitinib-induced vascular dysfunction.
2023-04-30 | GSE216453 | GEO
Project description:Aims: Novel cancer therapies leading to increased survivorship of cancer patients have been negated by a concomitant rise in cancer therapies-related cardiovascular toxicities. Sunitinib, a first line multi receptor tyrosine kinase inhibitor (TKI), has been reported to cause vascular dysfunction although the initiating mechanisms contributing to this side effect remain unknown. Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in endothelial cells (ECs); however, their roles in cancer therapies-related vascular toxicities remain underexplored. Methods and Results: We performed lncRNA expression profiling to identify potential lncRNAs that are dysregulated in human induced pluripotent stem cells-derived ECs (iPSC-ECs) treated with sunitinib. We show that the lncRNA hyaluronan synthase 2 antisense 1 (HAS2-AS1) is significantly diminished in sunitinib-treated iPSC-ECs. Sunitinib was found to downregulate HAS2-AS1 by an epigenetic mechanism involving hypermethylation. Depletion of HAS2-AS1 recapitulated sunitinib-induced detrimental effects on iPSC-ECs, whereas CRISPR-mediated activation of HAS2-AS1 reversed sunitinib-induced dysfunction. We confirm that HAS2-AS1 stabilizes the expression of its sense gene HAS2 via an RNA/mRNA heteroduplex formation. Knockdown of HAS2-AS1 led to reduced synthesis of hyaluronic acid (HA) and upregulation of ADAMTS5, an enzyme involved in extracellular matrix degradation, resulting in disruption of the endothelial glycocalyx which is critical for ECs. In vivo, sunitinib-treated mice showed reduced coronary flow reserve, accompanied by a reduction in has2os and degradation of the endothelial glycocalyx. Finally, we identify that treatment with high molecular-weight HA can prevent the deleterious effects of sunitinib both in vitro and in vivo by preserving the endothelial glycocalyx. Conclusions: Our findings highlight the importance of lncRNA-mediated regulation of the endothelial glycocalyx as an important determinant of sunitinib-induced vascular toxicity and reveal potential novel therapeutic avenues to attenuate sunitinib-induced vascular dysfunction.
2023-04-30 | GSE216452 | GEO
Project description:<p>The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer. </p>
2020-06-29 | MTBLS1764 | MetaboLights