A two-phase response of endothelial cells to hydrostatic pressure

Prystopiuk, Valeria; Fels, Benedikt; Simon, Caroline S.; Liashkovich, Ivan; Pasrednik, Dzmitry; Kronlage, Cornelius; Wedlich‐Söldner, Roland; Oberleithner, Hans; Fels, Johannes

doi:10.1242/jcs.206920

Cited by 38 publications

(43 citation statements)

References 91 publications

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“…As super-resolution imaging in the zebrafish embryo is technically difficult, we investigated whether Marcksl1 alters cortical actin organisation in HUVECs in culture. Like in zebrafish ECs and in a previous finding 19 , we also detected a meshwork of actin cytoskeleton at the apical cell cortex (Fig. 8b ).…”

Section: Resultssupporting

confidence: 89%

Marcksl1 modulates endothelial cell mechanoresponse to haemodynamic forces to control blood vessel shape and size

et al. 2020

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The formation of vascular tubes is driven by extensive changes in endothelial cell (EC) shape. Here, we have identified a role of the actin-binding protein, Marcksl1, in modulating the mechanical properties of EC cortex to regulate cell shape and vessel structure during angiogenesis. Increasing and depleting Marcksl1 expression level in vivo results in an increase and decrease, respectively, in EC size and the diameter of microvessels. Furthermore, endothelial overexpression of Marcksl1 induces ectopic blebbing on both apical and basal membranes, during and after lumen formation, that is suppressed by reduced blood flow. High resolution imaging reveals that Marcksl1 promotes the formation of linear actin bundles and decreases actin density at the EC cortex. Our findings demonstrate that a balanced network of linear and branched actin at the EC cortex is essential in conferring cortical integrity to resist the deforming forces of blood flow to regulate vessel structure.

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Section: Resultssupporting

confidence: 89%

Marcksl1 modulates endothelial cell mechanoresponse to haemodynamic forces to control blood vessel shape and size

et al. 2020

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“…We did not observe any changes in total cellular MYL2 phosphorylation in Western blot, which is in line with our work on endothelial cells (Prystopiuk et al, 2018). This phenomenon argues for localized phosphorylation of myosin light chains in the cell cortical area.…”

Section: Discussionsupporting

confidence: 92%

Protonation of Piezo1 Impairs Cell-Matrix Interactions of Pancreatic Stellate Cells

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by an acidic and fibrotic stroma. The extracellular matrix (ECM) causing the fibrosis is primarily formed by pancreatic stellate cells (PSCs). The effects of the altered biomechanics and pH landscape in the pathogenesis of PDAC, however, are poorly understood. Mechanotransduction in cells has been linked to the function of mechanosensitive ion channels such as Piezo1. Here, we tested whether this channel plays crucial roles in transducing mechanical signals in the acidic PDAC microenvironment. We performed immunofluorescence, Ca 2+ influx and intracellular pH measurements in PSCs and complemented them by live-cell imaging migration experiments in order to assess the function of Piezo1 channels in PSCs. We evaluated whether Piezo1 responds to changes of extracellular and/or intracellular pH in the pathophysiological range (pH 6.6 and pH 6.9, respectively). We validated our results using Piezo1-transfected HEK293 cells as a model system. Indeed, acidification of the intracellular space severely inhibits Piezo1-mediated Ca 2+ influx into PSCs. In addition, stimulation of Piezo1 channels with its activator Yoda1 accelerates migration of PSCs on a two-dimensional ECM as well as in a 3D setting. Furthermore, Yoda1-activated PSCs transmit more force to the surrounding ECM under physiological pH, as revealed by measuring the dislocation of microbeads embedded in the surrounding matrix. This is paralleled by an enhanced phosphorylation of myosin light chain isoform 9 after Piezo1 stimulation. Intriguingly, upon acidification, Piezo1 activation leads to the initiation of cell death and disruption of PSC spheroids. In summary, stimulating Piezo1 activates PSCs by inducing Ca 2+ influx which in turn alters the cytoskeletal architecture. This results in increased cellular motility and ECM traction, which can be useful for the cells to invade the surroundings and to detach from the tissue. However, in the presence of an acidic extracellular pH, although net Ca 2+ influx is reduced, Piezo1 activation leads to severe cell stress also limiting cellular viability. In conclusion, our results indicate a strong interdependence between environmental pH, the mechanical output of PSCs and stromal mechanics, which promotes early local invasion of PDAC cells.

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“…1b, c, e and f). This finding is consistent with a previous report that demonstrated an increase in the density of actin and activated phosphorylated myosin light chain at the EC cortex after chronic exposure to elevated hydrostatic pressure 19 . These observations therefore suggest ECs become stiffer after exposure to blood flow.…”

Section: Discussionsupporting

confidence: 94%

Marcksl1 modulates endothelial cell mechanoresponse to haemodynamic forces to control blood vessel shape and size

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et al. 2020

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The formation of vascular tubes is driven by extensive changes in endothelial cell (EC) shape. Here, we have identified a novel role of the actin-binding protein, Marcksl1, in modulating the mechanical properties of EC cortex to regulate cell shape and vessel structure during angiogenesis. Increasing and depleting Marcksl1 expression level in vivo resulted in an increase and decrease, respectively, in EC size and the diameter of microvessels. Furthermore, endothelial overexpression of Marcksl1 induced ectopic blebbing on both apical and basal membranes, during and after lumen formation, that is suppressed by reduced blood flow. High resolution imaging revealed that Marcksl1 promotes the formation of linear actin bundles and decreases actin density at the EC cortex. Our findings demonstrate that a balanced network of linear and branched actin at the EC cortex is essential in conferring cortical integrity to resist the deforming forces of blood flow to regulate vessel structure.

show abstract

A two-phase response of endothelial cells to hydrostatic pressure

Cited by 38 publications

References 91 publications

Marcksl1 modulates endothelial cell mechanoresponse to haemodynamic forces to control blood vessel shape and size

Marcksl1 modulates endothelial cell mechanoresponse to haemodynamic forces to control blood vessel shape and size

Protonation of Piezo1 Impairs Cell-Matrix Interactions of Pancreatic Stellate Cells

Marcksl1 modulates endothelial cell mechanoresponse to haemodynamic forces to control blood vessel shape and size

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