scholarly journals Role of Matrix Metalloproteinases in Multiwalled Carbon Nanotube-mediated Pulmonary and Systemic Inflammatory Activation

2021 ◽  
Author(s):  
Tamara L. Young ◽  
Ekaterina Mostovenko ◽  
Jesse L. Denson ◽  
Jessica G. Begay ◽  
Selita N. Lucas ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Significant Risk ◽  
Dependent Manner ◽  
Multiwalled Carbon ◽  
Endothelial Cell Function ◽  
Serum Peptide ◽  
Oropharyngeal Aspiration

Abstract Background: Multiwalled carbon nanotubes (MWCNT) are an increasingly utilized engineered nanomaterial that pose the potential for significant risk of exposure-related health outcomes. The mechanism(s) underlying MWCNT-induced toxicity to extrapulmonary sites are still being defined. MWCNT-induced serum-borne bioactivity appears to dysregulate systemic endothelial cell function. The serum compositional changes after MWCNT exposure have been identified as a surge of fragmented endogenous peptides, likely derived from matrix metalloproteinase (MMP) activity. In the present study, we utilize a broad-spectrum MMP inhibitor, Marimastat, along with a previously described oropharyngeal aspiration model of MWCNT administration to investigate the role of MMPs in MWCNT-derived serum peptide generation and endothelial bioactivity. Results: C57BL/6 mice were treated with Marimastat or vehicle by oropharyngeal aspiration 1h prior to MWCNT treatment. Pulmonary neutrophil infiltration and total bronchoalveolar lavage fluid protein increased in a dose-dependent manner, independent of MMP blockade. The lung cytokine profile similarly increased following MWCNT exposure for major inflammatory markers (IL-1β, IL-6, and TNFα), with minimal impact from MMP inhibition. However, serum peptidomic analysis revealed differential peptide compositional profiles, with MMP blockade abrogating MWCNT-derived serum peptide fragments. The serum, in turn, exhibited differential potency in terms of inflammatory bioactivity when incubated with primary murine cerebrovascular endothelial cells. Serum from MWCNT-treated mice led to inflammatory responses in endothelial cells that were significantly blunted with serum from Marimastat-treated mice. Conclusion: Thus, MWCNT exposure induced pulmonary inflammation that was largely independent of MMP activity, but generated circulating bioactive peptides through predominantly MMP-dependent pathways. This MWCNT-induced lung-derived bioactivity caused pathological consequences of endothelial inflammation and barrier disruption.

scholarly journals Pulmonary delivery of the broad-spectrum matrix metalloproteinase inhibitor marimastat diminishes multiwalled carbon nanotube-induced circulating bioactivity without reducing pulmonary inflammation

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Tamara L. Young ◽  
Ekaterina Mostovenko ◽  
Jesse L. Denson ◽  
Jessica G. Begay ◽  
Selita N. Lucas ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Matrix Metalloproteinase ◽  
Broad Spectrum ◽  
Inflammatory Responses ◽  
Pulmonary Inflammation ◽  
Significant Risk ◽  
Multiwalled Carbon ◽  
Endothelial Cell Function ◽  
Serum Peptide ◽  
Oropharyngeal Aspiration

Abstract Background Multiwalled carbon nanotubes (MWCNT) are an increasingly utilized engineered nanomaterial that pose the potential for significant risk of exposure-related health outcomes. The mechanism(s) underlying MWCNT-induced toxicity to extrapulmonary sites are still being defined. MWCNT-induced serum-borne bioactivity appears to dysregulate systemic endothelial cell function. The serum compositional changes after MWCNT exposure have been identified as a surge of fragmented endogenous peptides, likely derived from matrix metalloproteinase (MMP) activity. In the present study, we utilize a broad-spectrum MMP inhibitor, Marimastat, along with a previously described oropharyngeal aspiration model of MWCNT administration to investigate the role of MMPs in MWCNT-derived serum peptide generation and endothelial bioactivity. Results C57BL/6 mice were treated with Marimastat or vehicle by oropharyngeal aspiration 1 h prior to MWCNT treatment. Pulmonary neutrophil infiltration and total bronchoalveolar lavage fluid protein increased independent of MMP blockade. The lung cytokine profile similarly increased following MWCNT exposure for major inflammatory markers (IL-1β, IL-6, and TNF-α), with minimal impact from MMP inhibition. However, serum peptidomic analysis revealed differential peptide compositional profiles, with MMP blockade abrogating MWCNT-derived serum peptide fragments. The serum, in turn, exhibited differential potency in terms of inflammatory bioactivity when incubated with primary murine cerebrovascular endothelial cells. Serum from MWCNT-treated mice led to inflammatory responses in endothelial cells that were significantly blunted with serum from Marimastat-treated mice. Conclusions Thus, MWCNT exposure induced pulmonary inflammation that was largely independent of MMP activity but generated circulating bioactive peptides through predominantly MMP-dependent pathways. This MWCNT-induced lung-derived bioactivity caused pathological consequences of endothelial inflammation and barrier disruption.

scholarly journals Endothelial Cells in Emerging Viral Infections

2021 ◽  
Vol 8 ◽  
Author(s):  
Johanna Hol Fosse ◽  
Guttorm Haraldsen ◽  
Knut Falk ◽  
Reidunn Edelmann
Keyword(s):  
Endothelial Cells ◽  
Immune Responses ◽  
Vascular Function ◽  
Cell Function ◽  
Viral Infections ◽  
Host Immune System ◽  
Emerging Viruses ◽  
General Validity ◽  
Endothelial Cell Function

There are several reasons to consider the role of endothelial cells in COVID-19 and other emerging viral infections. First, severe cases of COVID-19 show a common breakdown of central vascular functions. Second, SARS-CoV-2 replicates in endothelial cells. Third, prior deterioration of vascular function exacerbates disease, as the most common comorbidities of COVID-19 (obesity, hypertension, and diabetes) are all associated with endothelial dysfunction. Importantly, SARS-CoV-2's ability to infect endothelium is shared by many emerging viruses, including henipaviruses, hantavirus, and highly pathogenic avian influenza virus, all specifically targeting endothelial cells. The ability to infect endothelium appears to support generalised dissemination of infection and facilitate the access to certain tissues. The disturbed vascular function observed in severe COVID-19 is also a prominent feature of many other life-threatening viral diseases, underscoring the need to understand how viruses modulate endothelial function. We here review the role of vascular endothelial cells in emerging viral infections, starting with a summary of endothelial cells as key mediators and regulators of vascular and immune responses in health and infection. Next, we discuss endotheliotropism as a possible virulence factor and detail features that regulate viruses' ability to attach to and enter endothelial cells. We move on to review how endothelial cells detect invading viruses and respond to infection, with particular focus on pathways that may influence vascular function and the host immune system. Finally, we discuss how endothelial cell function can be dysregulated in viral disease, either by viral components or as bystander victims of overshooting or detrimental inflammatory and immune responses. Many aspects of how viruses interact with the endothelium remain poorly understood. Considering the diversity of such mechanisms among different emerging viruses allows us to highlight common features that may be of general validity and point out important challenges.

Bradykinin activates the Janus-activated kinase/signal transducers and activators of transcription (JAK/STAT) pathway in vascular endothelial cells: localization of JAK/STAT signalling proteins in plasmalemmal caveolae

2000 ◽  
Vol 351 (1) ◽  
pp. 257-264 ◽  
Author(s):  
Hong JU ◽  
Virginia J. VENEMA ◽  
Haiying LIANG ◽  
M. Brennan HARRIS ◽  
Rong ZOU ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tyrosine Kinases ◽  
Cell Function ◽  
Nuclear Translocation ◽  
Serine Phosphorylation ◽  
Dependent Manner ◽  
Endothelial Cell Function ◽  
Signal Transducers ◽  
Stat Pathway ◽  
Signal Transducers And Activators

Bradykinin (BK) is an important physiological regulator of endothelial cell function. In the present study, we have examined the role of the Janus-activated kinase (JAK)/signal transducers and activators of transcription (STAT) pathway in endothelial signal transduction through the BK B2 receptor (B2R). In cultured bovine aortic endothelial cells (BAECs), BK activates Tyk2 of the JAK family of tyrosine kinases. Activation results in the tyrosine phosphorylation and subsequent nuclear translocation of STAT3. BK also activates the mitogen-activated p44 and p42 protein kinases, resulting in STAT3 serine phosphorylation. Furthermore, Tyk2 and STAT3 form a complex with the B2R in response to BK stimulation. Under basal conditions, Tyk2, STAT3 and the B2R are localized either partially or entirely in endothelial plasmalemmal caveolae. Following BK stimulation of BAECs, however, the B2R and STAT3 are translocated out of caveolae. Taken together, these data suggest that BK activates the JAK/STAT pathway in endothelial cells and that JAK/STAT signalling proteins are localized in endothelial caveolae. Moreover, caveolar localization of the B2R and STAT3 appears to be regulated in an agonist-dependent manner.

scholarly journals Pathological Roles of Mitochondrial Oxidative Stress and Mitochondrial Dynamics in Cardiac Microvascular Ischemia/Reperfusion Injury

Biomolecules ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 85 ◽  
Author(s):  
Hao Zhou ◽  
Sam Toan
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Function ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Mitochondrial Oxidative Stress ◽  
Endothelial Cell Function

Mitochondria are key regulators of cell fate through controlling ATP generation and releasing pro-apoptotic factors. Cardiac ischemia/reperfusion (I/R) injury to the coronary microcirculation has manifestations ranging in severity from reversible edema to interstitial hemorrhage. A number of mechanisms have been proposed to explain the cardiac microvascular I/R injury including edema, impaired vasomotion, coronary microembolization, and capillary destruction. In contrast to their role in cell types with higher energy demands, mitochondria in endothelial cells primarily function in signaling cellular responses to environmental cues. It is clear that abnormal mitochondrial signatures, including mitochondrial oxidative stress, mitochondrial fission, mitochondrial fusion, and mitophagy, play a substantial role in endothelial cell function. While the pathogenic role of each of these mitochondrial alterations in the endothelial cells I/R injury remains complex, profiling of mitochondrial oxidative stress and mitochondrial dynamics in endothelial cell dysfunction may offer promising potential targets in the search for novel diagnostics and therapeutics in cardiac microvascular I/R injury. The objective of this review is to discuss the role of mitochondrial oxidative stress on cardiac microvascular endothelial cells dysfunction. Mitochondrial dynamics, including mitochondrial fission and fusion, are critically discussed to understand their roles in endothelial cell survival. Finally, mitophagy, as a degradative mechanism for damaged mitochondria, is summarized to figure out its contribution to the progression of microvascular I/R injury.

scholarly journals Sensory neurons from dorsal root ganglia regulate endothelial cell function in extracellular matrix remodelling

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Alice Leroux ◽  
Bruno Paiva dos Santos ◽  
Jacques Leng ◽  
Hugo Oliveira ◽  
Joëlle Amédée
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Enzymatic Activity ◽  
Sensory Neurons ◽  
Bone Repair ◽  
Cell Function ◽  
Matrix Metalloproteinase 2 ◽  
Endothelial Cell Function ◽  
Angiogenic Markers

Abstract Background Recent physiological and experimental data highlight the role of the sensory nervous system in bone repair, but its precise role on angiogenesis in a bone regeneration context is still unknown. Our previous work demonstrated that sensory neurons (SNs) induce the osteoblastic differentiation of mesenchymal stem cells, but the influence of SNs on endothelial cells (ECs) was not studied. Methods Here, in order to study in vitro the interplay between SNs and ECs, we used microfluidic devices as an indirect co-culture model. Gene expression analysis of angiogenic markers, as well as measurements of metalloproteinases protein levels and enzymatic activity, were performed. Results We were able to demonstrate that two sensory neuropeptides, calcitonin gene-related peptide (CGRP) and substance P (SP), were involved in the transcriptional upregulation of angiogenic markers (vascular endothelial growth factor, angiopoietin 1, type 4 collagen, matrix metalloproteinase 2) in ECs. Co-cultures of ECs with SNs also increased the protein level and enzymatic activity of matrix metalloproteinases 2 and 9 (MMP2/MMP9) in ECs. Conclusions Our results suggest a role of sensory neurons, and more specifically of CGRP and SP, in the remodelling of endothelial cells extracellular matrix, thus supporting and enhancing the angiogenesis process.

scholarly journals Molecular Dambusters: What Is Behind Hyperpermeability in Bradykinin-Mediated Angioedema?

2021 ◽  
Author(s):  
Márta L. Debreczeni ◽  
Zsuzsanna Németh ◽  
Erika Kajdácsi ◽  
Henriette Farkas ◽  
László Cervenak
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Edema Formation ◽  
Endothelial Cell Function ◽  
Number Of Factors ◽  
Complex Scenario

AbstractIn the last few decades, a substantial body of evidence underlined the pivotal role of bradykinin in certain types of angioedema. The formation and breakdown of bradykinin has been studied thoroughly; however, numerous questions remained open regarding the triggering, course, and termination of angioedema attacks. Recently, it became clear that vascular endothelial cells have an integrative role in the regulation of vessel permeability. Apart from bradykinin, a great number of factors of different origin, structure, and mechanism of action are capable of modifying the integrity of vascular endothelium, and thus, may participate in the regulation of angioedema formation. Our aim in this review is to describe the most important permeability factors and the molecular mechanisms how they act on endothelial cells. Based on endothelial cell function, we also attempt to explain some of the challenging findings regarding bradykinin-mediated angioedema, where the function of bradykinin itself cannot account for the pathophysiology. By deciphering the complex scenario of vascular permeability regulation and edema formation, we may gain better scientific tools to be able to predict and treat not only bradykinin-mediated but other types of angioedema as well.

MG53 inhibits angiogenesis through regulating focal adhesion kinase signaling

2021 ◽  
Author(s):  
Jinling Dong ◽  
Haiyan Zhou ◽  
Yongjie Li ◽  
Rong Li ◽  
Ni Chen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Focal Adhesion Kinase ◽  
Signaling Pathways ◽  
Focal Adhesion ◽  
Cell Function ◽  
Striated Muscle ◽  
Tube Formation ◽  
Dependent Manner ◽  
Endothelial Cell Function

Abstract Mitsugumin 53 (MG53), which is expressed predominantly in striated muscle, has been demonstrated to be a myokine/cardiokine secreted from striated muscle under specific conditions. The important roles of MG53 in non-striated muscle tissues have also been examined in multiple disease models. However, no previous study has implicated MG53 in the control of endothelial cell function. In order to explore the effects of MG53 on endothelial cells, human umbilical vein endothelial cells (HUVECs) were stimulated with recombinant human MG53 (rhMG53). Then rhMG53 uptake, focal adhesion kinase (FAK)/Src/Akt/ERK1/2 signaling pathway activation, cell migration and tube formation were determined in vitro. The efficacy of rhMG53 in regulating angiogenesis was also detected in postnatal mouse retinas. The results demonstrated that rhMG53 directly entered into endothelial cells in a cholesterol-dependent manner. The uptake rhMG53 directly bound to FAK in endothelial cells, which resulted in significant decrease of FAK phosphorylation at Y397. Accompanied by the dephosphorylation of FAK, rhMG53 uncoupled FAK-Src interaction and reduced the phosphorylation of Src at Y416. Consequently, the activation of FAK/Src downstream signaling pathways, such as Akt and ERK1/2, was also significantly inhibited by rhMG53. Furthermore, rhMG53 remarkably decreased HUVEC migration and tube formation in vitro and postnatal mouse retinal angiogenesis in vivo. Taken together, these data indicate that rhMG53 inhibits angiogenesis through regulating FAK/Src/Akt/ERK1/2 signaling pathways. This may provide a novel molecular mechanism for the impaired angiogenesis in ischemic diseases.

The Role of Lipids in the Mechanism of Thrombosis

1979 ◽  
Author(s):  
A. Nordϕy
Keyword(s):  
Fatty Acids ◽  
Endothelial Cells ◽  
Cell Function ◽  
Thrombus Formation ◽  
Spontaneous Release ◽  
Endothelial Cell Function ◽  
Dietary Fatty Acid Composition ◽  
Plasma Ffa

Recent discoveries have emphazised the close connection between factors involved both in thrombogenesis and in atherogenesis. Lipoproteins seem to have a direct effect both n platelets and endothelial cells. LDL increases the sensitivity of platelets to aggregating substances and reduce the spontaneous release of prostacyclin (PGI2)from endo thelial cells. HDL may partially counteract this effect of LDL on endothelial cells grown in culture. Albumin bound fatty acids have also profound effects on platelet and endothelial cell function. The dual effects of the prostaglandin precursor fatty acids from the linoleic and linolenic sequences make these fatty acids crucial with regard to the Production of thromboxane A2 platelets and prostacyclin in endothelial cells. It is suggested that manipulation with the dietary fatty acid composition and other situations which will induce significant changes in the quantity and quality of plasma FFA may favour thrombus formation by disturbing the homeostatic balance between the function of platelets and endothelial cells.

scholarly journals Role of ROS in Aβ42 Mediated Activation of Cerebral Endothelial Cells

2014 ◽  
Vol 3 ◽  
Author(s):  
Andrey Tsoy ◽  
Bauyrzhan Umbayev ◽  
Tamara Shalakhmetova ◽  
Sholpan Askarova
Keyword(s):  
Endothelial Cells ◽  
Actin Polymerization ◽  
Inflammatory Responses ◽  
Time Dependent ◽  
Ros Generation ◽  
Dependent Manner ◽  
Ros Production ◽  
Cerebral Endothelial Cells ◽  
Pre Treatment

Introduction. There is substantial evidence that the deposition of aggregated amyloid-beta peptide (Aβ) in brain parenchyma and brain vessels is the main cause of neuronal dysfunction and death in Alzheimer’s disease (AD). Aβ exhibits multiple cytotoxic effects on neurons and glial cells and causes dysfunction of the blood brain barrier (BBB). In AD brains, an increased deposition of Aβ in the cerebral vasculature has been found to be correlated with increased transmigration of blood-borne inflammatory cells and neurovascular inflammation. However, regulatory mediators of these processes remain to be elucidated. In this study, we examined the role of ROS in actin polymerization and expression of adhesion molecules (P-selectin) on the surface of the cerebral endothelial cells (CECs) that are activated by Aβ42.Materials and methods. Mouse BEnd3 line (ATCC) was used in this research. BEnd3 cells respond to Aβ treatment similarly to human primary CECs and are a common model to investigate CECs’ function. We used immortalized bEnd3 cells as the following: controls; cells incubated with Aβ42 for 10, 30, and 60 minutes; cells incubated with 30 mM of antioxidant N-acetylcysteine (NAC) for 1 hr; and, cells pre-treated with NAC followed by Aβ42 exposure. We measured DHE fluorescence to investigate intracellular ROS production. Immunofluorescent microscopy of anti-P-selectin and oregon green phalloidin was used to quantify the surface P-selectin expression and actin polymerization, and Western blot analysis was used to analyze total P-selectin expression.Results. The results of this study have demonstrated a significant time-dependent ROS accumulation after 10 minutes, 30 minutes, and 60 minutes of Aβ42 treatment, while Aβ42 stimulated ROS production in CECs was attenuated by pre-treatment with the NAC antioxidant. We also found that Aβ42 increased P-selectin fluorescence at the surface of bEnd3 cells in a time dependent manner in parallel to ROS elevation. However, total expression levels of P-selectin were not changed following exposure to Aβ42. Pre-treatment with NAC attenuated Aβ42 induced P-selectin localization, while NAC alone did not significantly affect P selectin localization. As a positive control, H2O2 also increased P-selectin expression on the cell surface, which peaked after 30 minutes of H2O2 treatment. Exposure of CECs with Aβ42 promoted actin polymerization, which peaked after 10 minutes of Aβ42 treatment, while no significant increase of F-actin intensity was observed when cells were pre-treated with NAC. H2O2 was able to mimic Aβ42 induced oxidative stress, causing increased actin polymerization with similar timing.Conclusions. The results of our study have indicated that Aβ42 induced accumulation of P-selectin on the surface of bEnd3 cells and promoted actin polymerization, and all these events were correlated with ROS generation. The rapid post-translational cell signaling response mediated by ROS may well represent an important physiological trigger of the microvascular inflammatory responses in AD and requires further investigations.

scholarly journals CD40/CD40L contributes to hypercholesterolemia-induced microvascular inflammation

2009 ◽  
Vol 296 (3) ◽  
pp. H689-H697 ◽  
Author(s):  
Karen Y. Stokes ◽  
LeShanna Calahan ◽  
Candiss M. Hamric ◽  
Janice M. Russell ◽  
D. Neil Granger
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
T Cell ◽  
Blood Cell ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Microvascular Dysfunction ◽  
Cd40 Ligand ◽  
Scid Mice ◽  
Endothelial Cell Function

Hypercholesterolemia is associated with phenotypic changes in endothelial cell function that lead to a proinflammatory and prothrombogenic state in different segments of the microvasculature. CD40 ligand (CD40L) and its receptor CD40 are ubiquitously expressed and mediate inflammatory responses and platelet activation. The objective of this study was to determine whether CD40/CD40L, in particular T-cell CD40L, contributes to microvascular dysfunction induced by hypercholesterolemia. Intravital microscopy was used to quantify blood cell adhesion in cremasteric postcapillary venules, endothelium-dependent vasodilation responses in arterioles, and microvascular oxidative stress in wild-type (WT) C57BL/6, CD40-deficient (−/−), CD40L−/−, or severe combined immune deficient (SCID) mice placed on a normal (ND) or high-cholesterol (HC) diet for 2 wk. WT-HC mice exhibited an exaggerated leukocyte and platelet recruitment in venules and impaired vasodilation responses in arterioles compared with ND counterparts. A deficiency of CD40, CD40L, or lymphocytes attenuated these responses to HC. The HC phenotype was rescued in CD40L−/− and SCID mice by a transfer of WT T cells. Bone marrow chimeras revealed roles for both vascular- and blood cell-derived CD40 and CD40L in the HC-induced vascular responses. Hypercholesterolemia induced an oxidative stress in both arterioles and venules of WT mice, which was abrogated by either CD40 or CD40L deficiency. The transfer of WT T cells into CD40L−/− mice restored the oxidative stress. These results implicate CD40/CD40L interactions between circulating cells and the vascular wall in both the arteriolar and venular dysfunction elicited by hypercholesterolemia and identify T-cell-associated CD40L as a key mediator of these responses.

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