scholarly journals Mechanosensing Piezo channels in tissue homeostasis including their role in lungs

2018 ◽  
Vol 8 (2) ◽  
pp. 204589401876739 ◽  
Author(s):  
Ming Zhong ◽  
Yulia Komarova ◽  
Jalees Rehman ◽  
Asrar B. Malik
Keyword(s):  
Endothelial Cells ◽  
Critical Role ◽  
Specific Inhibitor ◽  
Tissue Homeostasis ◽  
Cyclic Stretch ◽  
Cardiovascular Development ◽  
Mechanical Stimuli ◽  
Pulmonary Hemodynamics ◽  
Adult Mice ◽  
Piezo Channels

Piezo channels are deemed to constitute one of the most important family of mechanosensing ion channels since their discovery in 2010. With recent advances in identifying their topological structure and the discovery of the agonist Yoda1 as well as the specific inhibitor GsMTx4, it is now possible to study the mechanisms by which Piezo channels are involved in physiological and pathophysiological processes. During embryonic cardiovascular development, Piezo1 senses shear stress and promotes vasculature growth. In adult mice, Piezo1 mediates the release of nitric oxide and ATP from endothelial cells to regulate blood pressure. Piezo channels also play a crucial role in cell differentiation and tissue homeostasis by exquisite mechanical force sensing. Piezo channels are also abundantly expressed in lung tissues. As the lung is exposed to complex pulmonary hemodynamics and respiratory mechanics, cells in the lung, such as microvascular endothelial cells, bear mechanical forces from blood flow shear, pulsatile strain, static pressure, and cyclic stretch due to respiratory movement. These mechanical stimuli are involved in a serial of physiological function and pathophysiological processes of the lung, many of which Piezo channels may be the key player. Mutation of genes encoding Piezo channels are also associated with hereditary human diseases, thus highlighting the critical role of Piezo channels in both tissue homeostasis and disease.

scholarly journals Mechanoregulation of YAP and TAZ in Cellular Homeostasis and Disease Progression

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaomin Cai ◽  
Kuei-Chun Wang ◽  
Zhipeng Meng
Keyword(s):  
Cell Fate ◽  
Vascular System ◽  
Tissue Injury ◽  
Hippo Pathway ◽  
Critical Role ◽  
Cell Interaction ◽  
Tissue Growth ◽  
Cyclic Stretch ◽  
Mechanical Stimuli ◽  
Hemodynamic Forces

Biophysical cues, such as mechanical properties, play a critical role in tissue growth and homeostasis. During organ development and tissue injury repair, compressive and tensional forces generated by cell-extracellular matrix or cell-cell interaction are key factors for cell fate determination. In the vascular system, hemodynamic forces, shear stress, and cyclic stretch modulate vascular cell phenotypes and susceptibility to atherosclerosis. Despite that emerging efforts have been made to investigate how mechanotransduction is involved in tuning cell and tissue functions in various contexts, the regulatory mechanisms remain largely unknown. One of the challenges is to understand the signaling cascades that transmit mechanical cues from the plasma membrane to the cytoplasm and then to the nuclei to generate mechanoresponsive transcriptomes. YAP and its homolog TAZ, the Hippo pathway effectors, have been identified as key mechanotransducers that sense mechanical stimuli and relay the signals to control transcriptional programs for cell proliferation, differentiation, and transformation. However, the upstream mechanosensors for YAP/TAZ signaling and downstream transcriptome responses following YAP/TAZ activation or repression have not been well characterized. Moreover, the mechanoregulation of YAP/TAZ in literature is highly context-dependent. In this review, we summarize the biomechanical cues in the tissue microenvironment and provide an update on the roles of YAP/TAZ in mechanotransduction in various physiological and pathological conditions.

scholarly journals PKCα mediates acetylcholine-induced activation of TRPV4-dependent calcium influx in endothelial cells

2011 ◽  
Vol 301 (3) ◽  
pp. H757-H765 ◽  
Author(s):  
Ravi K. Adapala ◽  
Phani K. Talasila ◽  
Ian N. Bratz ◽  
David X. Zhang ◽  
Makoto Suzuki ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Calcium Release ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Specific Inhibitor ◽  
Receptor Potential ◽  
Cyclic Stretch ◽  
Mesenteric Arteries ◽  
Transient Receptor Potential Vanilloid

Transient receptor potential vanilloid channel 4 (TRPV4) is a polymodally activated nonselective cationic channel implicated in the regulation of vasodilation and hypertension. We and others have recently shown that cyclic stretch and shear stress activate TRPV4-mediated calcium influx in endothelial cells (EC). In addition to the mechanical forces, acetylcholine (ACh) was shown to activate TRPV4-mediated calcium influx in endothelial cells, which is important for nitric oxide-dependent vasodilation. However, the molecular mechanism through which ACh activates TRPV4 is not known. Here, we show that ACh-induced calcium influx and endothelial nitric oxide synthase (eNOS) phosphorylation but not calcium release from intracellular stores is inhibited by a specific TRPV4 antagonist, AB-159908. Importantly, activation of store-operated calcium influx was not altered in the TRPV4 null EC, suggesting that TRPV4-dependent calcium influx is mediated through a receptor-operated pathway. Furthermore, we found that ACh treatment activated protein kinase C (PKC) α, and inhibition of PKCα activity by the specific inhibitor Go-6976, or expression of a kinase-dead mutant of PKCα but not PKCε or downregulation of PKCα expression by chronic 12- O-tetradecanoylphorbol-13-acetate treatment, completely abolished ACh-induced calcium influx. Finally, we found that ACh-induced vasodilation was inhibited by the PKCα inhibitor Go-6976 in small mesenteric arteries from wild-type mice, but not in TRPV4 null mice. Taken together, these findings demonstrate, for the first time, that a specific isoform of PKC, PKCα, mediates agonist-induced receptor-mediated TRPV4 activation in endothelial cells.

scholarly journals Roles of miR-17-92 Cluster in Cardiovascular Development and Common Diseases

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Huanyu Gu ◽  
Zhuyuan Liu ◽  
Lei Zhou
Keyword(s):  
Cardiovascular Disease ◽  
Small Rna ◽  
Normal Development ◽  
Cardiac Development ◽  
Critical Role ◽  
Tissue Homeostasis ◽  
Mirna Cluster ◽  
Cardiovascular Development ◽  
Rna Molecules ◽  
Precise Control

MicroRNAs (miRNAs and miRs) are a large class of noncoding, single-stranded, small RNA molecules. The precise control of their expression is essential for keeping tissue homeostasis and normal development of organisms. Thus, unbalanced expression of miRNAs is a hallmark of many diseases. Two to dozens of miRNAs can form into a miRNA cluster, and the miR-17-92 cluster is one of them. Although firstly described as an oncogenic miRNA cluster, the miR-17-92 cluster has also been found to play critical role in normal cardiac development and cardiovascular disease. This review focuses on the characteristics and functions of miR-17-92 cluster in heart.

scholarly journals The Mechanobiology of Endothelial-to-Mesenchymal Transition in Cardiovascular Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Shahrin Islam ◽  
Kristina I. Boström ◽  
Dino Di Carlo ◽  
Craig A. Simmons ◽  
Yin Tintut ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cardiovascular System ◽  
Therapeutic Interventions ◽  
Cell Phenotype ◽  
Cardiovascular Development ◽  
Mechanical Stimuli ◽  
Mesenchymal Transition ◽  
Pulsatile Pressure ◽  
Endothelial To Mesenchymal Transition

Endothelial cells (ECs) lining the cardiovascular system are subjected to a highly dynamic microenvironment resulting from pulsatile pressure and circulating blood flow. Endothelial cells are remarkably sensitive to these forces, which are transduced to activate signaling pathways to maintain endothelial homeostasis and respond to changes in the environment. Aberrations in these biomechanical stresses, however, can trigger changes in endothelial cell phenotype and function. One process involved in this cellular plasticity is endothelial-to-mesenchymal transition (EndMT). As a result of EndMT, ECs lose cell-cell adhesion, alter their cytoskeletal organization, and gain increased migratory and invasive capabilities. EndMT has long been known to occur during cardiovascular development, but there is now a growing body of evidence also implicating it in many cardiovascular diseases (CVD), often associated with alterations in the cellular mechanical environment. In this review, we highlight the emerging role of shear stress, cyclic strain, matrix stiffness, and composition associated with EndMT in CVD. We first provide an overview of EndMT and context for how ECs sense, transduce, and respond to certain mechanical stimuli. We then describe the biomechanical features of EndMT and the role of mechanically driven EndMT in CVD. Finally, we indicate areas of open investigation to further elucidate the complexity of EndMT in the cardiovascular system. Understanding the mechanistic underpinnings of the mechanobiology of EndMT in CVD can provide insight into new opportunities for identification of novel diagnostic markers and therapeutic interventions.

Effect of Combined Cyclic Stretch and Fluid Shear Stress on Endothelial Cell Morphological Responses

2005 ◽  
Vol 127 (3) ◽  
pp. 374-382 ◽  
Author(s):  
Tomas B. Owatverot ◽  
Sara J. Oswald ◽  
Yong Chen ◽  
Jeremiah J. Wille ◽  
Frank C-P Yin
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Time Course ◽  
Fluid Shear Stress ◽  
Cyclic Stretch ◽  
Mechanical Stimuli ◽  
Cell Orientation ◽  
Fluid Shear ◽  
Aortic Endothelial Cells

Endothelial cells in vivo are normally subjected to multiple mechanical stimuli such as stretch and fluid shear stress (FSS) but because each stimulus induces magnitude-dependent morphologic responses, the relative importance of each stimulus in producing the normal in vivo state is not clear. Using cultured human aortic endothelial cells, this study first determined equipotent levels of cyclic stretch, steady FSS, and oscillatory FSS with respect to the time course of cell orientation. We then tested whether these levels of stimuli were equipotent in combination with each other by imposing simultaneous cyclic stretch and steady FSS or cyclic stretch and oscillatory FSS so as to reinforce or counteract the cells’ orientation responses. Equipotent levels of the three stimuli were 2% cyclic stretch at 2%∕s, 80dynes∕cm2 steady FSS and 20±10dynes∕cm2 oscillatory FSS at 20dyne∕cm2-s. When applied in reinforcing fashion, cyclic stretch and oscillatory, but not steady, FSS were additive. Both pairs of stimuli canceled when applied in counteracting fashion. These results indicate that this level of cyclic stretch and oscillatory FSS sum algebraically so that they are indeed equipotent. In addition, oscillatory FSS is a stronger stimulus than steady FSS for inducing cell orientation. Moreover, arterial endothelial cells in vivo are likely receiving a stronger stretch than FSS stimulus.

Regulation of endothelial cell branching morphogenesis by endogenous chemokine stromal-derived factor-1

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2703-2711 ◽  
Author(s):  
Ombretta Salvucci ◽  
Lei Yao ◽  
Sabrina Villalba ◽  
Agatha Sajewicz ◽  
Stefania Pittaluga ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Pertussis Toxin ◽  
Neutralizing Antibodies ◽  
Critical Role ◽  
Branching Morphogenesis ◽  
Cardiovascular Development

Abstract The chemokine stromal-derived factor-1 (SDF-1) and its unique receptor, CXCR4, are required for normal cardiovascular development, but a critical role for SDF-1 in postnatal vascular remodeling and the mechanisms underlying SDF-1/CXCR-4 vasculogenesis are unclear. Here we show that SDF-1 is expressed by the vascular endothelium from selected healthy and tumor tissues. In vitro, primary endothelial cells constitutively express SDF-1 that is detected in the cytoplasm, on the cell surface, and in the culture supernatant. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) increase SDF-1 expression in endothelial cells. In functional studies, pertussis toxin and antibodies to SDF-1 or CXCR-4 disrupt extracellular matrix-dependent endothelial cell tube formation in vitro. This morphogenic process is associated with time-dependent modulation of surface CXCR-4 expression that changes from being diffuse to being polarized and subsequently lost. In vivo, pertussis toxin and neutralizing antibodies directed at SDF-1 inhibit growth factor–dependent neovascularization. These results indicate that SDF-1/CXCR-4 identifies VEGF- and bFGF-regulated autocrine signaling systems that are essential regulators of endothelial cell morphogenesis and angiogenesis.

scholarly journals Passage dependent changes in nuclear and cytoskeleton structures of endothelial cells under laminar shear stress or cyclic stretch

2021 ◽  
Vol 7 (7) ◽  
pp. 327
Author(s):  
Yizhi Jiang ◽  
Nathaniel Witt ◽  
Julie Y. Ji
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Laminar Flow ◽  
Image Data ◽  
Cyclic Strain ◽  
Cyclic Stretch ◽  
Mechanical Stimuli ◽  
Laminar Shear Stress ◽  
External Forces ◽  
Induced Changes

<p class="abstract"><strong>Background:</strong> The ability of vascular endothelium to sense and respond to the mechanical stimuli generated by blood flow is pivotal in maintaining arterial homeostasis. A steady laminar flow tends to provide athero-protective effect via regulating endothelial functions, vascular tone, and further remodeling process. As arterial aging appeared to be an independent risk factor of cardiovascular diseases, it is critical to understand the effects of cell senescence on endothelial dysfunction under dynamic mechanical stimuli.</p><p class="abstract"><strong>Methods:</strong> In this study, we investigated the morphological responses of aortic endothelial cells toward laminar flow or cyclic stretch. Automated image recognition methods were applied to analyze image data to avoid bias. Differential patterns of morphological adaptations toward distinct mechanical stimuli were observed, and the shear-induced changes were found to be more associated with cell passages than that of cyclic strain.  </p><p class="abstract"><strong>Results:</strong> Our results demonstrated that the cytoskeleton and nuclear structural adaptations in endothelial cells toward laminar flow were altered over prolonged culture, suggesting that the failure of senescent endothelial cells to adapt to the applied shear stress morphologically could be one of the contributors to endothelial dysfunctions during vascular aging.</p><p class="abstract"><strong>Conclusions:</strong> Results indicated that cells were able to adjust their cytoskeleton and nuclear alignment and nuclear shapes in response to the applied mechanical stimuli, and that the shear-induced changes were more dependent on PD levels, where cells with higher PDL were more responsive to external forces.</p>

scholarly journals BLNK/BTK: Novel Components in the NF-kappa B Pathways of Endothelial Cells in Diabetic Condition

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A318-A319
Author(s):  
Madhu V Singh ◽  
Thomas Wong ◽  
Ayotunde O Dokun
Keyword(s):  
Endothelial Cells ◽  
B Cell ◽  
Signaling Pathways ◽  
High Glucose ◽  
Prolonged Exposure ◽  
Umbilical Vein ◽  
Critical Role ◽  
Specific Inhibitor ◽  
Venn Diagram ◽  
Nfkb Pathway

Abstract Peripheral artery disease (PAD) is atherosclerotic occlusion of vessel outside the heart that most commonly affects the lower extremities. The effects of PAD-related ischemia are exacerbated under diabetic hyperglycemic conditions. Under ischemic conditions, an adaptive induction of the NFkB pathways is in vascular endothelial cells is required for recovery. We have recently shown that prolonged exposure of cells to high glucose before ischemia resulted in impairment of the canonical NFkB pathway through decrease in IkBa degradation. However, the signaling pathways involved in hyperglycemia and ischemia mediated effects on the NFkB pathways are not well understood. Since the NFkB signaling pathways propagate through a cascade of phosphorylation events, we used arrays of antibodies to approximately 100 proteins known to participate in the NFkB pathway to identify the changes in their phosphorylation states in human umbilical vein endothelial cells (HUVEC). Cells grown for three days either in culture medium with normal glucose (LG) or high glucose (HG) were subjected to ischemia for 24 hours (LGI and HGI, respectively). Cell lysates were then incubated with the array of antibodies printed on glass slides (Full Moon Biosystems, Sunnyvale, CA) and fluorescent signals were digitally recorded and normalized. The change in protein phosphorylation was calculated by dividing the intensity of the phosphorylated spot by the signal intensity of the corresponding non-phosphorylated spot for each protein. Differential expression between LG and LGI samples, and HG and HGI were calculated by dividing the phosphorylation ratio of the LGI and HGI with that of the LG and HG controls, respectively. A threshold of 1.5-fold increase or decrease was used to determine changes. Compared to the LG, LGI samples had 26 protein sites with increased phosphorylation whereas 36 sites had decreased phosphorylation. Similarly, compared to HG, HGI samples increased phosphorylation of 25 protein sites and decreased phosphorylation of 40 sites. A Venn-diagram analysis of LGI and HGI sites revealed 8 sites with an increase and 12 sites with a decrease in phosphorylation were specific to HGI. Pathway analyses using bioinformatics tools on 65 modulated phosphorylation sites in HGI (represented by 35 genes) suggested involvement of B cell linker/adapter protein (BLNK)/Bruton’s tyrosine kinase (BTK) that are critical for B cell antigen receptor (BCR)-coupled signaling. BTK expression in EC was confirmed by immunoblotting. Inhibition of BTK by a specific inhibitor terreic acid restored IkBa degradation in EC grown in high glucose suggesting a critical role of BLNK/BTK in diabetic ischemia. Thus, we have identified BLNK/BTK as potentially new components of the NFkB pathway in endothelial cells that contributes to the poor recovery during hyperglycemic ischemia.

Glycated Collagen Decreased Endothelial Cell Fibronectin Alignment in Response to Cyclic Stretch Via Interruption of Actin Alignment

2014 ◽  
Vol 136 (10) ◽  
Author(s):  
Dannielle S. Figueroa ◽  
Steven F. Kemeny ◽  
Alisa Morss Clyne
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Matrix Metalloproteinase ◽  
Cyclic Stretch ◽  
Matrix Metalloproteinase 2 ◽  
Mechanical Stimuli ◽  
Protein Alignment ◽  
Chronic Hyperglycemia ◽  
Native Collagen ◽  
In Cells

Hyperglycemia is a defining characteristic of diabetes, and uncontrolled blood glucose in diabetes is associated with accelerated cardiovascular disease. Chronic hyperglycemia glycates extracellular matrix (ECM) collagen, which can lead to endothelial cell dysfunction. In healthy conditions, endothelial cells respond to mechanical stimuli such as cyclic stretch (CS) by aligning their actin cytoskeleton. Other cell types, specifically fibroblasts, align their ECM in response to CS. We previously demonstrated that glycated collagen inhibits endothelial cell actin alignment in response to CS. The aim of this study was to determine the effect of glycated collagen on ECM remodeling and protein alignment in response to stretch. Porcine aortic endothelial cells (PAEC) seeded on native or glycated collagen coated elastic substrates were exposed to 10% CS. Cells on native collagen aligned subcellular fibronectin fibers in response to stretch, whereas cells on glycated collagen did not. The loss of fibronectin alignment was due to inhibited actin alignment in response to CS, since fibronectin alignment did not occur in cells on native collagen when actin alignment was inhibited with cytochalasin. Further, while ECM protein content did not change in cells on native or glycated collagen in response to CS, degradation activity decreased in cells on glycated collagen. Matrix metalloproteinase 2 (MMP-2) and membrane-associated type 1 matrix metalloproteinase (MT1-MMP) protein levels decreased, and therefore MMP-2 activity also decreased. These MMP changes may relate to c-Jun N-terminal kinase (Jnk) phosphorylation inhibition with CS, which has previously been linked to focal adhesion kinase (FAK). These data demonstrate the importance of endothelial cell actin tension in remodeling and aligning matrix proteins in response to mechanical stimuli, which is critical to vascular remodeling in health and disease.

The molecular mechanism of mechanotransduction in vascular homeostasis and disease

2020 ◽  
Vol 134 (17) ◽  
pp. 2399-2418
Author(s):  
Yoshito Yamashiro ◽  
Hiromi Yanagisawa
Keyword(s):  
Shear Stress ◽  
Blood Vessels ◽  
Vessel Wall ◽  
Vascular Diseases ◽  
Cell Interactions ◽  
Aortic Aneurysms ◽  
Cyclic Stretch ◽  
Mechanical Stimuli ◽  
Vascular Homeostasis ◽  
Matrix Cell

Abstract Blood vessels are constantly exposed to mechanical stimuli such as shear stress due to flow and pulsatile stretch. The extracellular matrix maintains the structural integrity of the vessel wall and coordinates with a dynamic mechanical environment to provide cues to initiate intracellular signaling pathway(s), thereby changing cellular behaviors and functions. However, the precise role of matrix–cell interactions involved in mechanotransduction during vascular homeostasis and disease development remains to be fully determined. In this review, we introduce hemodynamics forces in blood vessels and the initial sensors of mechanical stimuli, including cell–cell junctional molecules, G-protein-coupled receptors (GPCRs), multiple ion channels, and a variety of small GTPases. We then highlight the molecular mechanotransduction events in the vessel wall triggered by laminar shear stress (LSS) and disturbed shear stress (DSS) on vascular endothelial cells (ECs), and cyclic stretch in ECs and vascular smooth muscle cells (SMCs)—both of which activate several key transcription factors. Finally, we provide a recent overview of matrix–cell interactions and mechanotransduction centered on fibronectin in ECs and thrombospondin-1 in SMCs. The results of this review suggest that abnormal mechanical cues or altered responses to mechanical stimuli in EC and SMCs serve as the molecular basis of vascular diseases such as atherosclerosis, hypertension and aortic aneurysms. Collecting evidence and advancing knowledge on the mechanotransduction in the vessel wall can lead to a new direction of therapeutic interventions for vascular diseases.

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