NOTCH1 is a mechanosensor in adult arteries

Mack, Julia J.; Mosqueiro, Thiago; Archer, Brian J.; Jones, William M.; Sunshine, Hannah; Faas, Guido C.; Briot, Anaïs; Aragón, Raquel; Su, Trent; Romay, Milagros C.; McDonald, Austin I.; Kuo, Chien-Nan; Lizama, Carlos O.; Lane, Timothy F.; Zovein, Ann C.; Fang, Yun; Tarling, Elizabeth J.; Vallim, Thomas Q. de Aguiar; Navab, Mohamad; Fogelman, Alan M.; Bouchard, Louis; Iruela‐Arispe, M. Luisa

doi:10.1038/s41467-017-01741-8

Cited by 251 publications

(282 citation statements)

References 71 publications

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“…This study provides the first evidence that hPSC-ECs possess mechano sensors that are activated at very low shear stress magnitudes (< 1 dyne/cm 2 ) to elicit cytoskeletal rearrangement. NOTCH1 is a well-established shear stress sensor in ECs since knockdown of NOTCH1 in mature arterial EC can affect their alignment to the flow direction (Mack et al, 2017). Contrary to this, we did not observe a direct correlation between NOTCH1 expression and cellular alignment.…”

contrasting

confidence: 99%

Determination of critical shear stress for maturation of human pluripotent stem cell‐derived endothelial cells towards an arterial subtype

Arora

Lam

Cheung

et al. 2019

Biotech & Bioengineering

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Human pluripotent stem cell‐derived endothelial cells (hPSC‐ECs) present an attractive alternative to primary EC sources for vascular grafting. However, there is a need to mature them towards either an arterial or venous subtype. A vital environmental factor involved in the arteriovenous specification of ECs during early embryonic development is fluid shear stress; therefore, there have been attempts to employ adult arterial shear stress conditions to mature hPSC‐ECs. However, hPSC‐ECs are naïve to fluid shear stress, and their shear responses are still not well understood. Here, we used a multiplex microfluidic platform to systematically investigate the dose‐time shear responses on hPSC‐EC morphology and arterial‐venous phenotypes over a range of magnitudes coincidental with physiological levels of embryonic and adult vasculatures. The device comprised of six parallel cell culture chambers that were individually linked to flow‐setting resistance channels, allowing us to simultaneously apply shear stress ranging from 0.4 to 15 dyne/cm 2. We found that hPSC‐ECs required up to 40 hr of shear exposure to elicit a stable phenotypic change. Cell alignment was visible at shear stress <1 dyne/cm 2, which was independent of shear stress magnitude and duration of exposure. We discovered that the arterial markers NOTCH1 and EphrinB2 exhibited a dose‐dependent increase in a similar manner beyond a threshold level of 3.8 dyne/cm 2, whereas the venous markers COUP‐TFII and EphB4 expression remained relatively constant across different magnitudes. These findings indicated that hPSC‐ECs were sensitive to relatively low magnitudes of shear stress, and a critical level of ~4 dyne/cm 2 was sufficient to preferentially enhance their maturation into an arterial phenotype for future vascular tissue engineering applications.

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confidence: 99%

Determination of critical shear stress for maturation of human pluripotent stem cell‐derived endothelial cells towards an arterial subtype

Arora

Lam

Cheung

et al. 2019

Biotech & Bioengineering

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“…Even though the downstream players of the notch pathway remain to be established in the OFT, these results validate previous observations, suggesting that klf2a acts upstream of Notch signaling in the endocardium (Donat et al, 2018;Samsa et al, 2015;Vermot et al, 2009). Considering that Notch has been proposed to be mechanosensitive in blood vessels (Mack et al, 2017), an attractive hypothesis is that the Klf2-Notch axis could be a general mechanosensitive cascade in endothelial cells. In that case, it would be interesting to address notch activity in a flow related context, similarly to what is currently being done with Nf-kb, Klf2a, and other flow responsive pathways (Feaver et al, 2013).…”

Section: Klf2a Modulates Notch Signaling Specifically In the Oft Endosupporting

confidence: 87%

Mechanically activated Piezo channels control outflow tract valve development through Yap1 and Klf2-Notch signaling axis

Duchemin

Vignes

Vermot

2019

Preprint

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Mechanical forces are well known for modulating heart valve developmental programs. Yet, it is still unclear how genetic programs and mechanosensation interact during heart valve development. Here, we assessed the mechanosensitive pathways involved during zebrafish outflow tract (OFT) valve development in vivo. Our results show that the hippo effector Yap1, Klf2, and the Notch signaling pathway are all essential for OFT valve morphogenesis in response to mechanical forces, albeit active in different cell layers. Furthermore, we show that Piezo and TRP mechanosensitive channels are essential for regulating these pathways. In addition, live reporters reveal that piezo controls Klf2 and Notch activity in the endothelium and Yap1 expression in the smooth muscle progenitors to coordinate OFT valve morphogenesis. Together, this work identifies a unique morphogenetic program during OFT valve formation and places Piezo as a central modulator of the cell response to forces in this process.

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“…FSS acting on ECs also activates Notch1 signaling at cell-cell contacts [26][27][28] . KD of LPHN2, but not LPHN1 or LPHN3, completely blocked the production of the Notch intracellular domain (ICD) in response to FSS ( Figure 4A and 4B).…”

Section: Latrophilin-2 In Fss Activation Of Notch and Smadsmentioning

confidence: 99%

Latrophilins are essential for endothelial junctional fluid shear stress mechanotransduction

Tanaka

Prendergast

Hintzen

et al. 2020

Preprint

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Endothelial cell (EC) responses to fluid shear stress (FSS) are crucial for vascular development, adult physiology and disease. PECAM1 is an important transducer but earlier events remain poorly understood. We therefore investigated heterotrimeric G proteins in FSS sensing.Knockdown (KD) in ECs of single Gα proteins had little effect but combined depletion of Gαi and Gαq/11 blocked all known PECAM1-dependent responses. Re-expression of Gαi2 and Gαq but not Gαi1 and Gαi3 rescued these effects. Sequence alignment and mutational studies identified that K307 in Gαi2 and Gq/11 (Q306 in Gαi1/3), determines participation in flow signaling. We developed pull-down assays for measuring Gα activation and found that this residue, localized to the GPCR interface, determines activation by FSS. We developed a protocol for affinity purification of GPCRs on activated Gα's, which identified latrophilins (ADGRLs) as specific upstream interactors for Gαi2 and Gq/11. Depletion of latrophilin-2 blocked EC activation of Gαi2 and Gαq, downstream events in vitro, and flow-dependent vascular morphogenesis in zebrafish embryos. Surprisingly, latrophilin-2 depletion also blocked flow activation of two additional pathways activated at cell-cell junctions, Smad1/5 and Notch1, independently of Gα proteins.Latrophilins are thus central mediators of junctional shear stress mechanotransduction via Gα protein-dependent and -independent mechanisms.

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NOTCH1 is a mechanosensor in adult arteries

Cited by 251 publications

References 71 publications

Determination of critical shear stress for maturation of human pluripotent stem cell‐derived endothelial cells towards an arterial subtype

Determination of critical shear stress for maturation of human pluripotent stem cell‐derived endothelial cells towards an arterial subtype

Mechanically activated Piezo channels control outflow tract valve development through Yap1 and Klf2-Notch signaling axis

Latrophilins are essential for endothelial junctional fluid shear stress mechanotransduction

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