The guidance receptor plexin D1 is a mechanosensor in endothelial cells

Mehta, Vedanta; Pang, Kar Lai; Rozbeský, Daniel; Nather, Katrin; Keen, A.; Lachowski, Dariusz; Kong, Y.; Karia, Dimple; Ameismeier, Michael; Huang, Jianhua; Fang, Yun; Hernández, Armando E. del Río; Reader, John S.; Jones, E.Y.; Tzima, Ellie

doi:10.1038/s41586-020-1979-4

Cited by 163 publications

(157 citation statements)

References 40 publications

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“…Expression of the NOS3 gene is regulated by the transcription factors, KLF2 and KLF4. KLF2 and KLF4 are known to be regulated in endothelial cells by blood flow via the mechanosensor, PLEXIND1 48 . Flow-dependent endothelial cell-derived NO is a freely diffusible, but short-lived molecule.…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide prevents aortic valve calcification by S-nitrosylation of USP9X to activate NOTCH signaling

Majumdar

Manivannan

Basu

et al. 2020

Preprint

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Calcific aortic valve disease (CAVD) is an increasingly prevalent condition and endothelial dysfunction is implicated in its etiology. We previously identified nitric oxide (NO) as a calcification inhibitor by its activation of NOTCH1, which is genetically linked to human CAVD. Here, we show that NO rescues calcification by a S-nitrosylation-mediated mechanism in porcine aortic valve interstitial cells (pAVICs) and single cell RNA-seq demonstrated regulation of NOTCH pathway by NO. A unbiased proteomic approach to identify S-nitrosylated proteins in valve cells found enrichment of the ubiquitin proteasome pathway and implicated S-nitrosylation of USP9X in NOTCH regulation during calcification. Furthermore, S-nitrosylated USP9X was shown to deubiquitinate and stabilize MIB1 for NOTCH1 activation. Consistent with this, genetic deletion of Usp9x in mice demonstrated aortic valve disease and human calcified aortic valves displayed reduced S-nitrosylation of USP9X. These results demonstrate a novel mechanism by which S-nitrosylation dependent regulation of ubiquitin-associated pathway prevents CAVD.

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Section: Discussionmentioning

confidence: 99%

Nitric oxide prevents aortic valve calcification by S-nitrosylation of USP9X to activate NOTCH signaling

Majumdar

Manivannan

Basu

et al. 2020

Preprint

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“…The extracellular domain of several plexins has been shown to adopt different conformations ranging from a nearly closed, ring-like form to a more-open, chair-like form 17,47,48 . Very recently, a particular plexin, Plexin-D1, has been reported to sense shear stress-induced mechanical forces in endothelial cells 17 . This function in mechanosensation required the opening of the ring-like conformation of the Plexin-D1 extracellular domain, but was independent of the binding of semaphorins 17 .…”

Section: Discussionmentioning

confidence: 99%

“…Very recently, a particular plexin, Plexin-D1, has been reported to sense shear stress-induced mechanical forces in endothelial cells 17 . This function in mechanosensation required the opening of the ring-like conformation of the Plexin-D1 extracellular domain, but was independent of the binding of semaphorins 17 . This is in line with our findings in epithelial cells,…”

Section: Discussionmentioning

confidence: 99%

“…They are now recognized to be of central importance for cell-cell communication in multiple tissues and biological systems, such as the immune and bone system, as well as in cancer [14][15][16] . Very recently, Plexin-D1 has been shown to be activated by fluid shear stress-induced mechanical forces in vascular endothelial cells 17 . Whether plexins play a role in mechanosensation in epithelial cells is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Mechanochemical control of epidermal stem cell divisions by B-plexins

Chen

Javed

Kaiser

et al. 2020

Preprint

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The precise spatiotemporal control of cell proliferation is key to the morphogenesis of epithelial tissues. Epithelial cell divisions lead to tissue crowding and local changes in force distribution, which in turn suppress the rate of cell divisions. However, the molecular mechanisms underlying this mechanical feedback are largely unclear. Here, we identify a critical requirement of B-plexin transmembrane receptors in the response to crowding-induced mechanical forces during embryonic skin development. Epidermal stem cells lacking B-plexins fail to sense mechanical compression, resulting in disinhibition of the transcriptional coactivator YAP, hyperproliferation, and tissue overgrowth. Mechanistically, we show that B-plexins mediate mechanoresponses to crowding through stabilization of adhesive cell junctions and lowering of cortical stiffness. Finally, we provide evidence that the B-plexin-dependent mechanochemical feedback is also pathophysiologically relevant to limit tumor growth in basal cell carcinoma, the most common type of skin cancer. Our data uncover a central role of Bplexins in mechanosensation to couple cell density and cell division in development and disease.

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“…shear stress), triggering dynamic interactions with cytoskeletal elements. The shear stress exerted by blood flow, typically in the range of ~1-15 dyne/cm 2 [11][12][13][14][15][16], is known to be an important regulator of mechanotransduction in vascular physiology [17,18], including mechanosensory processes of actin-mediated stabilization of junctions [13,[19][20][21], followed by morphological remodeling [6,[22][23][24] and tension redistribution [25] such that cells can maintain or change their shape.…”

Section: Introductionmentioning

confidence: 99%

Biomechanical characterization of endothelial cells exposed to shear stress using acoustic force spectroscopy

Silvani

Romanov

Cox

et al. 2020

Preprint

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Characterizing mechanical properties of cells is important for understanding many cellular processes, such as cell movement, shape, and growth, as well as adaptation to changing environments. In this study, we explore mechanical properties of endothelial cells that form the biological barrier lining blood vessels, whose dysfunction leads to development of many cardiovascular disorders. Stiffness and contractile prestress of living endothelial cells were determined by Acoustic Force Spectroscopy (AFS) focusing on the displacement of functionalized microspheres located at the cell-cell periphery. The specific configuration of the acoustic microfluidic channel allowed us to develop a long-term dynamic culture protocol exposing cells to laminar flow, reaching shear stresses in the physiological range (i.e. 8 dyne cm-2) within 48 hours of barrier function maturation. A staircase-like sequence of increasing force steps, ranging from 186 pN to 3.5 nN, was applied in a single measurement revealing a force-dependent apparent stiffness in the kPa range. Moreover, our results show that different degrees of stiffening, defining the elastic behavior of the cell under different experimental conditions, i.e. static and dynamic, are caused by different levels of contractile prestress in the cytoskeleton, and are modulated by shear stress-mediated junction development and stabilization at cell borders. These results demonstrate that the AFS is capable of fast and high-throughput force measurements of adherent cells under conditions mimicking their native microenvironment, and thus revealing the shear stress dependence of mechanical properties of neighbouring endothelial cells.

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The guidance receptor plexin D1 is a mechanosensor in endothelial cells

Cited by 163 publications

References 40 publications

Nitric oxide prevents aortic valve calcification by S-nitrosylation of USP9X to activate NOTCH signaling

Nitric oxide prevents aortic valve calcification by S-nitrosylation of USP9X to activate NOTCH signaling

Mechanochemical control of epidermal stem cell divisions by B-plexins

Biomechanical characterization of endothelial cells exposed to shear stress using acoustic force spectroscopy

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