Endothelial Cell Calcium Signaling during Barrier Function and Inflammation

Dalal, Prarthana; Müller, William A.; Sullivan, David P.

doi:10.1016/j.ajpath.2019.11.004

Cited by 137 publications

(121 citation statements)

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“…Calcium signaling in endothelial cells is a highly regulated process (31) Therefore, loss of endothelial barrier integrity and monocyte adhesion which are integral to atherosclerosis may be directly related to Piezo1 (19,48). Although our findings provide insight into the relationship between Piezo1 activation and deleterious effects on endothelial cells, it is important to note that development of atherosclerosis is a chronic process and is best studied in animals.…”

Section: Discussionmentioning

confidence: 99%

“…In endothelial cells, shear stress regulates levels of intracellular calcium ([Ca 2+ ]i) and downstream calcium signaling (23,(29)(30)(31). We evaluated the magnitude and duration of shear stress forces that affected [Ca 2+ ]i in human umbilical vein endothelial cells (HUVECs).…”

Section: Fluid Shear Stress Induced [Ca 2 + ]I Overload Is Force Andmentioning

confidence: 99%

“…Disruption of normal cell-to-cell contacts in the vascular endothelium accompanies excessive shear force and leads to an inflammatory response characterized by monocyte adhesion (3,31). Having demonstrated that shear force activates Piezo1 which can disrupt AJs and form paracellular gaps in confluent monolayers we next evaluated the effects of Piezo1 on endothelial cell activation and adhesion protein expression, which are two of the early processes in atherosclerosis (41).…”

Section: Blockade Of Trpv4 Inhibits Piezo1-mediated Monocyte Adhesionmentioning

confidence: 99%

“…Under physiological conditions, the amplitude and frequency of [Ca 2+ ]i oscillations in endothelial cells maintain cellular integrity, but stimulation by inflammatory mediators such as histamine, bradykinin and thrombin increases intracellular calcium up to 10 fold (31). High sustained [Ca 2+ ]i, leading to calcium overload, alters normal calcium signaling pathways and causes cytoskeletal disorganization and AJs disassembly.Together these processes facilitate transendothelial migration of leukocytes.High blood pressure and shear stress also have been associated with endothelial dysfunction(1,3,13,31,42). High blood pressure or shear stress-mediated calcium overload contributes to cytoskeletal disorganization, AJs disassembly and leukocyte transendothelial migration(2,10,11,17,29,40).…”

mentioning

confidence: 99%

“…Moreover, TRPV4 was responsible for Piezo1 initiated cell retraction and paracellular gap formation in monolayer cultures. Thus, the combined actions of both Piezo1 and TRPV4 may contribute to the endothelial vascular barrier dysfunction in hypertension.Fluid shear stress caused by blood flow is a major determinant of vascular remodeling and arterial tone and can lead to the development of atherosclerosis(31,40). High shear stress-mediated calcium signaling activates endothelial cells, cytoskeleton remodeling, and production of inflammatory cytokines and chemokines which facilitate leukocyte rolling, adhesion, and transendothelial migration(31).…”

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confidence: 99%

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Shear stress-induced pathological changes in endothelial cells occur through Piezo1 activation of TRPV4

Swain

Liddle

2020

Preprint

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AbstractAlthough the ion channels Piezo1 and TRPV4 have been implicated in high venous pressure- and fluid shear stress-induced vascular hyperpermeability, they have been described as working independently. Moreover, the mechanism by which Piezo1 and TRPV4 channels in endothelial cells execute the same function is poorly understood. Here we demonstrate that Piezo1 regulates TRPV4 channel activation in endothelial cells and that Piezo1-mediated TRPV4 channel opening is a function of the strength and duration of fluid shear stress. Application of the Piezo1 antagonist, GsMTx4, completely blocked the elevation in intracellular calcium ([Ca2+]i) induced by both fluid shear stress and the Piezo1 agonist, Yoda1. High and prolonged shear stress caused sustained [Ca2+]i elevation which required TRPV4 opening and was responsible for fluid shear stress- and Piezo1-mediated disruption of adherens junctions and actin remodeling. We found that Piezo1’s effects were mediated by phospholipase A2 activation. Blockade of TRPV4 channels with the selective TRPV4 blocker, HC067047, prevented the loss of endothelial cell integrity and actin disruption induced by Yoda1 or shear stress and prevented Piezo1-induced monocyte adhesion to endothelial cell monolayers. These findings demonstrate that Piezo1 activation by fluid shear stress initiates a calcium signal that causes TRPV4 opening which in turn is responsible for the sustained phase calcium elevation that triggers pathological events in endothelial cells.

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Section: Discussionmentioning

confidence: 99%

Section: Fluid Shear Stress Induced [Ca 2 + ]I Overload Is Force Andmentioning

confidence: 99%

Section: Blockade Of Trpv4 Inhibits Piezo1-mediated Monocyte Adhesionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Shear stress-induced pathological changes in endothelial cells occur through Piezo1 activation of TRPV4

Swain

Liddle

2020

Preprint

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Discovery of metabolic markers for the discrimination of Helwingia species based on bioactivity evaluation, plant metabolomics, and network pharmacology

Wang

Chen

Song

et al. 2022

Rapid Comm Mass Spectrometry

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Rationale Helwingia japonica (HJ), a traditional medicinal plant, is commonly used for the treatment of dysentery, blood in the stool, and scald burns. Three major HJ species, Helwingia japonica (Thunb.) Dietr. (QJY), Helwingia himalaica Hook. f. et Thoms. ex C. B. Clarke, and Helwingia chinensis Batal., share great similarities in both morphology and chemical constituents. The discrimination of medicinal plants directly affects their pharmacological and clinical effects. Here, we solved the taxonomy uncertainty of these three HJ species and explored the discrimination and study of other traditional medicines (TMs). Methods First, the anti‐inflammatory effects of the three HJ species were compared using lipopolysaccharide (LPS)‐induced inflammatory responses in mouse leukemia cells of monocyte macrophage (RAW) 264.7 cells. Then, plant metabolomics were performed in 48 batches of samples to discover chemical markers for discriminating different HJ species. Finally, network pharmacology was applied to explore the linkages among constituents, targets, and signaling pathways. Results In vitro experiments showed that the QJY exhibited the most potential anti‐inflammatory activities. Meanwhile, 172 compounds were tentatively identified and eight metabolites with higher relative content in QJY were designated as chemical markers to distinguish QJY and the other two species. According to the property of absorbed in vivo, threonic acid, arginine, and tyrosine were selected to construct a component–target–pathway network. The network pharmacology analysis confirmed that the chemotaxonomy differentiation was consistent with the bioactive assessment. Conclusions The present study demonstrates that bioactivity evaluation integrated with plant metabolomics and network pharmacology could be used as an effective approach to discriminate different TMs and discover the active compounds.

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Mechanisms of immune effector cell‐associated neurotoxicity syndrome after CAR‐T treatment

et al. 2022

WIREs Mechanisms of Disease

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Chimeric antigen receptor T-cell (CAR-T) treatment has revolutionized the landscape of cancer therapy with significant efficacy on hematologic malignancy, especially in relapsed and refractory B cell malignancies. However, unexpected serious toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) still hamper its broad application. Clinical trials using CAR-T cells targeting specific antigens on tumor cell surface have provided valuable information about the characteristics of ICANS. With unclear mechanism of ICANS after CAR-T treatment, unremitting efforts have been devoted to further exploration. Clinical findings from patients with ICANS strongly indicated existence of overactivated peripheral immune response followed by endothelial activationinduced blood-brain barrier (BBB) dysfunction, which triggers subsequent central nervous system (CNS) inflammation and neurotoxicity. Several animal models have been built but failed to fully replicate the whole spectrum of ICANS in human. Hopefully, novel and powerful technologies like single-cell analysis may help decipher the precise cellular response within CNS from a different perspective when ICANS happens. Moreover, multidisciplinary cooperation among the subjects of immunology, hematology, and neurology will facilitate better understanding about the complex immune interaction between the peripheral, protective barriers, and CNS in ICANS. This review elaborates recent findings about ICANS after CAR-T treatment from bed to bench, and discusses the potential cellular and molecular mechanisms that may promote effective management in the future.

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Endothelial Cell Calcium Signaling during Barrier Function and Inflammation

Cited by 137 publications

References 58 publications

Shear stress-induced pathological changes in endothelial cells occur through Piezo1 activation of TRPV4

Shear stress-induced pathological changes in endothelial cells occur through Piezo1 activation of TRPV4

Discovery of metabolic markers for the discrimination of Helwingia species based on bioactivity evaluation, plant metabolomics, and network pharmacology

Mechanisms of immune effector cell‐associated neurotoxicity syndrome after CAR‐T treatment

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