SUN1/2 Are Essential for RhoA/ROCK-Regulated Actomyosin Activity in Isolated Vascular Smooth Muscle Cells

Porter, Lauren Jade; Minaisah, Rose-Marie; Ahmed, Sultan; Ali, Seema; Norton, Rosemary; Zhang, Qiuping; Ferraro, Elisa; Molenaar, Christiaan; Holt, Mark R.; Cox, Susan; Fountain, Samuel J.; Shanahan, Catherine M.; Warren, Derek

doi:10.3390/cells9010132

Cited by 29 publications

(31 citation statements)

References 47 publications

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“…In agreement with this, mutations in proteins associated with the LINC complex affect tissues subject to high mechanical forces. Actomyosin contractility increases SUN2's association with lamins in vascular smooth muscle cells, thus remodeling interactions at the INM and altering the balance between actin and microtubule associations with the ONM [88]. Downregulation of Nesprin-2 or non-muscle myosin II, both involved in the formation and maintenance of TAN lines and actin perinuclear caps, results in similar alterations of the expression of genes associated with the epithelial-to-mesenchymal transition [18,24,89,90].…”

Section: Actin Around the Nucleus And Gene Expressionmentioning

confidence: 99%

Actin on and around the Nucleus

Davidson

Cadot

2021

Trends in Cell Biology

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Actin plays roles in many important cellular processes, including cell motility, organelle movement, and cell signaling. The discovery of transmembrane actin-binding proteins at the outer nuclear membrane (ONM) raises the exciting possibility that actin can play a role in direct force transmission to the nucleus and the genome at its interior. Actin-dependent nucleus displacement was first described a decade ago. We are now gaining a more detailed understanding of its mechanisms, as well as new roles for actin during mitosis and meiosis, for gene expression, and in the cell's response to mechanical stimuli. Here we review these recent developments, the actin-binding proteins involved, the tissue specificity of these mechanisms, and methods developed to reconstitute and study this interaction in vitro. Preamble: The Nucleus and the Surrounding ActinThe nucleus was once considered a simple, static reservoir for the genetic material of the cell. We now know that it plays a wide range of roles, from controlling mechanical sensing to regulating gene expression. Similarly, actin structures around the nuclear envelope (NE) (see Glossary) were first described decades ago, but their role was initially unclear. The discovery of the transmembrane linker of nucleoskeleton to cytoskeleton (LINC) complexes in the early 21st century established that nuclear lamins and chromatin inside the nucleus mechanically connect to the cytoskeleton outside the nucleus [1]. The NE and the actin cytoskeleton (Boxes 1 and 2) are now generating renewed interest as active partners in gene expression. NE proteins are implicated in a wide variety of diseases and their connections to actin may thus play important roles in many physiological processes, likely in a tissue-dependent manner (Figure 1).Here, we discuss the recently described roles that NE-associated actin plays, including displacement of the nucleus within the cell, NE breakdown (NEBD), gene expression, and cellular responses to stress. An entire parallel field has also risen from the (long controversial) idea that actin can assemble and perform functions inside the nucleus, although we do not discuss nuclear actin in this review. Actin Functions around the NucleusActin for Positioning Nuclei: Anchoring and Moving Nuclei into Position Actin mediates nuclear movement to a particular functional position within the cell in many tissues and is responsible for maintaining this position. One striking example is the interkinetic movement of nuclei in pseudostratified epithelia, first described in 1935 [2], in which nuclei are displaced from the basal to the apical surface of the cell to undergo mitosis. The roles of actin and microtubules in mediating nuclear movement differ significantly depending on the tissue, most likely due to the geometry and the thickness of the epithelial layer, which determine the mechanical constraints and the distance the nucleus must move [3]. Microtubules are required for nuclear movement in the highly elongated cells of the rodent neocortex, whereas in the zebra...

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Section: Actin Around the Nucleus And Gene Expressionmentioning

confidence: 99%

Actin on and around the Nucleus

Davidson

Cadot

2021

Trends in Cell Biology

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“…In this study we develop and validate an approach for screening isolated VSMC contraction using cell area as a reporter. The assay uses polyacrylamide hydrogels that are easily fabricated and mimic the rigidity of the physiological elastic arterial wall ( Minaisah et al, 2016 ; Porter et al, 2020 ). Moreover, we show that combined with TFM, this technique allows investigation into factors that regulate both VSMC morphology and traction stress generation.…”

Section: Introductionmentioning

confidence: 99%

Using Polyacrylamide Hydrogels to Model Physiological Aortic Stiffness Reveals that Microtubules Are Critical Regulators of Isolated Smooth Muscle Cell Morphology and Contractility

et al. 2022

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Vascular smooth muscle cells (VSMCs) are the predominant cell type in the medial layer of the aortic wall and normally exist in a quiescent, contractile phenotype where actomyosin-derived contractile forces maintain vascular tone. However, VSMCs are not terminally differentiated and can dedifferentiate into a proliferative, synthetic phenotype. Actomyosin force generation is essential for the function of both phenotypes. Whilst much is already known about the mechanisms of VSMC actomyosin force generation, existing assays are either low throughput and time consuming, or qualitative and inconsistent. In this study, we use polyacrylamide hydrogels, tuned to mimic the physiological stiffness of the aortic wall, in a VSMC contractility assay. Isolated VSMC area decreases following stimulation with the contractile agonists angiotensin II or carbachol. Importantly, the angiotensin II induced reduction in cell area correlated with increased traction stress generation. Inhibition of actomyosin activity using blebbistatin or Y-27632 prevented angiotensin II mediated changes in VSMC morphology, suggesting that changes in VSMC morphology and actomyosin activity are core components of the contractile response. Furthermore, we show that microtubule stability is an essential regulator of isolated VSMC contractility. Treatment with either colchicine or paclitaxel uncoupled the morphological and/or traction stress responses of angiotensin II stimulated VSMCs. Our findings support the tensegrity model of cellular mechanics and we demonstrate that microtubules act to balance actomyosin-derived traction stress generation and regulate the morphological responses of VSMCs.

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“…The former consists of Nesprin 1-4 in humans, which are embedded in the ONM. Of interests, Nesprins can physically interact with (i) plectin, a binding partner of intermediate filaments (IFs), (ii) kinesin and dynein, which are the motor proteins of microtubules, and (iii) directly with F-actin [183][184][185][186][187]. This means, that Nesprins can get in contact with all kinds of cytosolic cytoskeletal filament systems, rendering them the perfect adhesion proteins for transmitting cytoskeletal tension, including actomyosin contractility, into the nucleus.…”

Section: The Gist Of the Matter: Nuclear Mechanotransductionmentioning

confidence: 99%

From the Matrix to the Nucleus and Back: Mechanobiology in the Light of Health, Pathologies, and Regeneration of Oral Periodontal Tissues

et al. 2021

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Among oral tissues, the periodontium is permanently subjected to mechanical forces resulting from chewing, mastication, or orthodontic appliances. Molecularly, these movements induce a series of subsequent signaling processes, which are embedded in the biological concept of cellular mechanotransduction (MT). Cell and tissue structures, ranging from the extracellular matrix (ECM) to the plasma membrane, the cytosol and the nucleus, are involved in MT. Dysregulation of the diverse, fine-tuned interaction of molecular players responsible for transmitting biophysical environmental information into the cell’s inner milieu can lead to and promote serious diseases, such as periodontitis or oral squamous cell carcinoma (OSCC). Therefore, periodontal integrity and regeneration is highly dependent on the proper integration and regulation of mechanobiological signals in the context of cell behavior. Recent experimental findings have increased the understanding of classical cellular mechanosensing mechanisms by both integrating exogenic factors such as bacterial gingipain proteases and newly discovered cell-inherent functions of mechanoresponsive co-transcriptional regulators such as the Yes-associated protein 1 (YAP1) or the nuclear cytoskeleton. Regarding periodontal MT research, this review offers insights into the current trends and open aspects. Concerning oral regenerative medicine or weakening of periodontal tissue diseases, perspectives on future applications of mechanobiological principles are discussed.

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SUN1/2 Are Essential for RhoA/ROCK-Regulated Actomyosin Activity in Isolated Vascular Smooth Muscle Cells

Cited by 29 publications

References 47 publications

Actin on and around the Nucleus

Actin on and around the Nucleus

Using Polyacrylamide Hydrogels to Model Physiological Aortic Stiffness Reveals that Microtubules Are Critical Regulators of Isolated Smooth Muscle Cell Morphology and Contractility

From the Matrix to the Nucleus and Back: Mechanobiology in the Light of Health, Pathologies, and Regeneration of Oral Periodontal Tissues

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