Piezo1 channels are mechanosensors in human fetoplacental endothelial cells

Morley, Lara; Shi, Jing; Gaunt, Hannah J.; Hyman, Adam J.; Webster, Peter J.; Williams, Courtney; Forbes, Karen; Walker, James J.; Simpson, Nigel; Beech, David J.

doi:10.1093/molehr/gay033

Cited by 48 publications

(49 citation statements)

References 43 publications

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“…Similar to the membrane potential observations from intact endothelium ( Figure 4), Smpd3 fro/fro caused Piezo1 channels to become inactivating (Figure 5a-c). Consistent with these data, the observed channel activity had the expected unitary current size of Piezo1 channels at -80 mV 15,18,19 and was suppressed by Gd 3+ , a blocker of Piezo1 channels 14,19 (Figure 5d-f). GW4869 similarly suppressed the sustained response to flow in excised patches (Supplementary Figure S2).…”

Section: Bacterial Sphingomyelinase Enhances Piezo1-dependent Ca 2+ Esupporting

confidence: 82%

“…In 2014 an important molecular component was revealed as the Piezo1 channel [11][12][13] , a Ca 2+ -permeable nonselective cationic channel that seems to have as its primary function the sensing of mechanical force and its transduction into cellular response [14][15][16][17] . Endothelial Piezo1 is relevant to vascular maturation in the embryo, response to shear stress in adult endothelial cells in vitro and in vivo, and the disease of generalized lymphatic dysplasia [11][12][13][18][19][20][21][22][23][24][25] . It alone confers shear stress response on otherwise resistant cells and responds quickly and reversibly in membrane patches excised from endothelial cells, suggesting a membrane-delimited, perhaps direct, ability to sense shear stress 11,12,18,19 .…”

Section: Introductionmentioning

confidence: 99%

“…Endothelial Piezo1 is relevant to vascular maturation in the embryo, response to shear stress in adult endothelial cells in vitro and in vivo, and the disease of generalized lymphatic dysplasia [11][12][13][18][19][20][21][22][23][24][25] . It alone confers shear stress response on otherwise resistant cells and responds quickly and reversibly in membrane patches excised from endothelial cells, suggesting a membrane-delimited, perhaps direct, ability to sense shear stress 11,12,18,19 . It does not inactivate in response to sustained flow and so impacts continuously until flow ceases 11,19,24,25 .…”

Section: Introductionmentioning

confidence: 99%

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Sphingomyelinase disables Piezo1 channel inactivation to enable sustained response to mechanical force

Shi

Hyman

Vecchis

et al. 2019

Preprint

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Piezo1 channels are determinants of vascular responses to fluid flow. They importantly provide sustained response to flow, but this property contrasts with the rapid inactivation that has become a hallmark of the channels in heterologous overexpression studies. Here we reveal a mechanism by which blood vessels disable inactivation to enable sustained physiological response. Creation of a molecular model of Piezo1 channel in defined lipid membranes suggested potential modulation by sphingomyelin 2 and its product ceramide. Biological relevance was indicated by the observation that exogenous sphingomyelinase enhanced Piezo1-mediated Ca 2+ entry in cultured endothelial cells. We therefore hypothesised that endogenous sphingomyelinase suppresses channel inactivation. Remarkably, in endothelium freshly-isolated from murine artery, neutral sphingomyelinase inhibitors or genetic disruption of sphingomyelin phosphodiesterase 3 (SMPD3) caused flow-and pressure-activated Piezo1 channels to become inactivating. SMPD3 retained its ability to disable inactivation in cell-free membrane patches, providing evidence for a membrane localised effect. The data suggest that inherent inactivation of Piezo1 channels is disabled by enzymatic control of lipid environment to enable physiological response to mechanical force. random order determined by the genotype of litters. Data were generated in pairs (control mice and Smpd3 fro/fro mice) and data sets compared statistically by independent t-test without assuming equal variance. Paired t-tests were used when comparing data before and after application of flow or a substance to the same membrane patch or cell. One-way ANOVA followed by Tukey posthoc test was used for comparing multiple groups. Statistical significance was considered to exist at probability (P)

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Section: Bacterial Sphingomyelinase Enhances Piezo1-dependent Ca 2+ Esupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Sphingomyelinase disables Piezo1 channel inactivation to enable sustained response to mechanical force

Shi

Hyman

Vecchis

et al. 2019

Preprint

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“…Together with the maternal uteroplacental circulation, the fetoplacental vasculature is essential for placental perfusion and determines fetal growth and successful pregnancy outcome [38,104]. Piezo type mechanosensitive ion channel component 1 ( PIEZO1 ), is an important molecular marker of blood flow in the placenta and has the potential to be a new therapeutic target for the treatment of placental vascular diseases [105]. Switching B cell complex subunit SWAP70 is involved in regulating migration and invasion of trophoblast cells during the processes of embryonic implantation as well as placentation [106].…”

Section: Discussionmentioning

confidence: 99%

Placenta Transcriptome Profiling in Intrauterine Growth Restriction (IUGR)

Majewska

Lipka

Paukszto

et al. 2019

IJMS

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Intrauterine growth restriction (IUGR) is a serious pathological complication associated with compromised fetal development during pregnancy. The aim of the study was to broaden knowledge about the transcriptomic complexity of the human placenta by identifying genes potentially involved in IUGR pathophysiology. RNA-Seq data were used to profile protein-coding genes, detect alternative splicing events (AS), single nucleotide variant (SNV) calling, and RNA editing sites prediction in IUGR-affected placental transcriptome. The applied methodology enabled detection of 37,501 transcriptionally active regions and the selection of 28 differentially-expressed genes (DEGs), among them 10 were upregulated and 18 downregulated in IUGR-affected placentas. Functional enrichment annotation indicated that most of the DEGs were implicated in the processes of inflammation and immune disorders related to IUGR and preeclampsia. Additionally, we revealed that some genes (S100A13, GPR126, CTRP1, and TFPI) involved in the alternation of splicing events were mainly implicated in angiogenic-related processes. Significant SNVs were overlapped with 6533 transcripts and assigned to 2386 coding sequence (CDS), 1528 introns, 345 5’ untranslated region (UTR), 1260 3’UTR, 918 non-coding RNA (ncRNA), and 10 intergenic regions. Within CDS regions, 543 missense substitutions with functional effects were recognized. Two known mutations (rs4575, synonymous; rs3817, on the downstream region) were detected within the range of AS and DEG candidates: PA28β and PINLYP, respectively. Novel genes that are dysregulated in IUGR were detected in the current research. Investigating genes underlying the IUGR is crucial for identification of mechanisms regulating placental development during a complicated pregnancy.

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“…Overexpressed mouse and human Piezo1 channels were originally shown to be activated by Yoda1 with an EC50 of 17.1 and 26.6 μM respectively [24]. Native Piezo1 channels too have responded to Yoda1 at low micromolar concentrations [19], [21], [29]. However EC50 values were shown to be much lower (2.51 mM for stably overexpressed Piezo1 and 0.23 mM for native channels in human umbilical vein endothelial cells) recently [26].…”

Section: Piezo1 Agonist Regulates Insulin Release From Primary Mouse mentioning

confidence: 99%

Piezo1 channel agonist mimics high glucose as a stimulator of insulin release

Deivasikamani

Dhayalan

Mughal

et al. 2018

Preprint

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Objective: Glucose and hypotonicity induced cell swelling stimulate insulin release from pancreatic b-cells but the mechanisms are poorly understood. Recently, Piezo1 was identified as a mechanically-activated nonselective Ca 2+ permeable cationic channel in a range of mammalian cells. As cell swelling induced insulin release could be through stimulation of Ca 2+ permeable stretch activated channels, we hypothesised a role for Piezo1 in cell swelling induced insulin release. Methods:Two rat b-cell lines (INS-1 and BRIN-BD11) and freshly-isolated mouse pancreatic islets were studied. Intracellular Ca 2+ measurements were performed using the fura-2 Ca 2+ indicator dye. Piezo1 agonist Yoda1, a competitive antagonist of Yoda1 (Dooku1) and an inactive analogue of Yoda1 (2e) were used as chemical probes. Piezo1 mRNA and insulin secretion were measured by RT-PCR and ELISA respectively.Results: Piezo1 mRNA was detected in both b-cell lines and mouse islets. Yoda1 evoked Ca 2+ entry which was inhibited by Yoda1 antagonist Dooku1 as well as other Piezo1 inhibitors gadolinium and ruthenium red, and not mimicked by 2e. Yoda1, but not 2e, stimulated Dooku1-sensitive insulin release from b-cells and pancreatic islets. Hypotonicity and high glucose increased intracellular Ca 2+ and enhanced Yoda1 Ca 2+ influx responses. Pre-treatment with ruthenium red significantly reduced hypotonicity induced insulin release from b-cells and pancreatic islets. Conclusion:The data show that Piezo1 channel agonist induces insulin release from b-cell lines and mouse pancreatic islets suggesting a role for Piezo1 in cell swelling induced insulin release. Hence Piezo1 agonists have a potential to be used as enhancers of insulin release.

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Piezo1 channels are mechanosensors in human fetoplacental endothelial cells

Cited by 48 publications

References 43 publications

Sphingomyelinase disables Piezo1 channel inactivation to enable sustained response to mechanical force

Sphingomyelinase disables Piezo1 channel inactivation to enable sustained response to mechanical force

Placenta Transcriptome Profiling in Intrauterine Growth Restriction (IUGR)

Piezo1 channel agonist mimics high glucose as a stimulator of insulin release

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