The molecular mechanism of mechanotransduction in vascular homeostasis and disease

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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Matrix mechanotransduction mediated by thrombospondin-1/integrin/YAP signaling pathway in the remodeling of blood vessels

10.1101/814533 ◽

2019 ◽

Author(s):

Yoshito Yamashiro ◽

Bui Quoc Thang ◽

Karina Ramirez ◽

Seung Jae Shin ◽

Tomohiro Kohata ◽

...

Keyword(s):

Blood Vessels ◽

Signaling Pathway ◽

Vessel Wall ◽

Focal Adhesions ◽

Cell Interactions ◽

Cyclic Stretch ◽

List Type ◽

Matrix Cell ◽

Thrombospondin 1 ◽

Nuclear Shuttling

AbstractRationaleThe extracellular matrix (ECM) initiates mechanical cues and transduces intracellular signaling through matrix-cell interactions. In the blood vessels, additional mechanical cues derived from the pulsatile blood flow and pressure play a pivotal role in homeostasis and disease development. Currently, the nature of the cues from ECM and how they coordinate with a mechanical microenvironment in large blood vessels to maintain the integrity of the vessel wall are not fully understood.ObjectiveThe aim of this study was to elucidate the crucial mediator(s) and molecular signaling pathway(s) involved in matrix mechanotransduction during remodeling of the vessel wall.Methods and ResultsWe performed secretome analysis using rat vascular smooth muscle cells (SMCs) under cyclic stretch and examined matrix-cell interactions and cell behavior. We found that the matricellular protein thrombospondin-1 (Thbs1) was secreted upon cyclic stretch and bound to integrin αvβ1, thereby recruiting vinculin and establishing focal adhesions. RNA-sequence (RNA-seq) analysis revealed that deletion of Thbs1 in vitro markedly affected the target gene expression of Yes-associated protein (YAP). Consistently, we found that Thbs1 promotes nuclear shuttling of YAP in response to cyclic stretch, which depends on the small GTPase Rap2 and Hippo pathway, and is not influenced by alteration of actin fibers. Deletion of Thbs1 in mice inhibited Thbs1/integrin/YAP signaling, leading to maladaptive remodeling of the aorta in response to pressure overload by transverse aortic constriction (TAC), whereas it suppressed neointima formation upon carotid artery ligation, exerting context-dependent effects on the vessel wall.ConclusionsThbs1 serves as a mechanical stress-triggered extracellular mediator of mechanotransduction that acts via integrin αvβ1 to establish focal adhesions and promotes nuclear shuttling of YAP. We thus propose a novel mechanism of matrix mechanotransduction centered on Thbs1, connecting mechanical stimuli to YAP signaling during vascular remodeling in vivo.Subject codesVascular DiseaseGenetically Altered and Transgenic ModelsVascular BiologyCell Signaling/Signal Transduction

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Matrix mechanotransduction mediated by thrombospondin-1/integrin/YAP in the vascular remodeling

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1919702117 ◽

2020 ◽

Vol 117 (18) ◽

pp. 9896-9905 ◽

Cited By ~ 6

Author(s):

Yoshito Yamashiro ◽

Bui Quoc Thang ◽

Karina Ramirez ◽

Seung Jae Shin ◽

Tomohiro Kohata ◽

...

Keyword(s):

Blood Vessels ◽

Intracellular Signaling ◽

Vascular Remodeling ◽

Vessel Wall ◽

Focal Adhesions ◽

Small Gtpase ◽

Cyclic Stretch ◽

Matricellular Protein ◽

Mechanical Stimuli ◽

Thrombospondin 1

The extracellular matrix (ECM) initiates mechanical cues that activate intracellular signaling through matrix–cell interactions. In blood vessels, additional mechanical cues derived from the pulsatile blood flow and pressure play a pivotal role in homeostasis and disease development. Currently, the nature of the cues from the ECM and their interaction with the mechanical microenvironment in large blood vessels to maintain the integrity of the vessel wall are not fully understood. Here, we identified the matricellular protein thrombospondin-1 (Thbs1) as an extracellular mediator of matrix mechanotransduction that acts via integrin αvβ1 to establish focal adhesions and promotes nuclear shuttling of Yes-associated protein (YAP) in response to high strain of cyclic stretch. Thbs1-mediated YAP activation depends on the small GTPase Rap2 and Hippo pathway and is not influenced by alteration of actin fibers. Deletion of Thbs1 in mice inhibited Thbs1/integrin β1/YAP signaling, leading to maladaptive remodeling of the aorta in response to pressure overload and inhibition of neointima formation upon carotid artery ligation, exerting context-dependent effects on the vessel wall. We thus propose a mechanism of matrix mechanotransduction centered on Thbs1, connecting mechanical stimuli to YAP signaling during vascular remodeling in vivo.

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Influence of Intermittent Pneumatic Compression on Wall Shear Stress and Nitric Oxide Levels

ASME 2011 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2011-53670 ◽

2011 ◽

Author(s):

Ganesh Swaminathan ◽

Suraj Thyagaraj ◽

Francis Loth ◽

Susan McCormick ◽

Hisham Bassiouny

Keyword(s):

Nitric Oxide ◽

Shear Stress ◽

Wall Shear Stress ◽

Blood Vessels ◽

Healthy Subjects ◽

Vascular Diseases ◽

Intermittent Pneumatic Compression ◽

Peripheral Vascular ◽

Peripheral Vascular Diseases ◽

Wall Shear

Wall shear stress (WSS) in blood vessels has been shown to play an important role in the development of atherosclerosis. In particular, regions of low and oscillating WSS have been shown to correlate with the localization of atherosclerosis. Thus, we hypothesize that increasing the WSS for patients with peripheral vascular diseases (PVD) will either reduce PVD severity or slow its progression. We analyzed WSS changes from a study by Delis et al. on 32 limbs of PVD patients [1]. Results show that intermittent pneumatic compression (IPC) increases mean WSS by 170% and 240% in PVD patients and healthy subjects, respectively. Peak WSS was found to increase by 93% and 40% in PVD patients and healthy subjects, respectively. In addition, we examined changes in NOX level with use of IPC on five limbs from PVD patients. Our study demonstrated increased NOx levels in subjects after IPC. Further research is needed to determine the benefits of IPC for PVD patients.

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Testing Different Hypotheses of Vascular Homeostasis Based on Mechanical Stress or Strain in Image-Based Models Using an Inverse Method

ASME 2011 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2011-53213 ◽

2011 ◽

Author(s):

Shahrokh Zeinali-Davarani ◽

Seungik Baek

Keyword(s):

Inverse Method ◽

Arterial Wall ◽

Vascular Tissue ◽

Optimization Method ◽

Cyclic Stretch ◽

Mechanical Stimuli ◽

Vascular Homeostasis ◽

Physiological Conditions ◽

Mechanical Quantity ◽

Mechanical Homeostasis

Various hypotheses are previously suggested to describe the tendency of vascular tissue to adapt in response to alterations in mechanical stimuli. It is still a matter of controversy which mechanical quantity governs or correlates well with the adaptation, contributing to the mechanical homeostasis. A computational tool that can distinguish between different hypotheses under various physiological conditions may help better understanding of the governing rules. Recently, an inverse optimization method has been developed to estimate the optimal spatial distributions of arterial wall thickness and material anisotropy of image-based models while satisfying a homeostatic condition assumed [1]. The same numerical method can be utilized to investigate the consequent optimal structures resulting from different hypotheses for the mechanical homeostasis. We consider three hypotheses for a homeostatic state based on intramural stress or cyclic stretch and examine their effects on the optimized distributions of thickness and anisotropy. The results show the capability of the presented method in discriminating different hypotheses of vascular homeostasis with image-based models, the validity of which requires more experimental data.

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Effect of Wall Shear Stress on Abdominal Aortic Aneurysm Expansion: Study With Longitudinal Patient Images

ASME 2012 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2012-80350 ◽

2012 ◽

Author(s):

B. Zambrano ◽

A. Dupay ◽

F. Jaberi ◽

W. Lee ◽

S. Baek

Keyword(s):

Shear Stress ◽

Wall Shear Stress ◽

Open Surgery ◽

Vascular Diseases ◽

Aortic Aneurysms ◽

Maximum Diameter ◽

Abdominal Aortic ◽

Reduce Risk ◽

Wall Shear

Abdominal Aortic Aneurysms (AAA), a focal enlargement of abdominal aorta, is a form of vascular diseases that affects large part of the population. It can cause the mortality up to 90% of the cases when it ruptures. Currently, the best known treatment to reduce risk is open surgery or endovascular repair. Since the risk of such surgery repair is high, in most patients with AAAs< 55mm in its maximum diameter the surgical treatment is postponed. An effort to enhance the accuracy of the risk assessment and to prevent AAA’s growth and rupture is being made, but the mechanisms promoting AAAs growth are still largely unknown. AAAs can be affected by different factors, among those, hemodynamics is known to play important roles in AAA initiation and progression. Particularly, the wall shear stress is believed to contribute to AAA expansion and rupture. For the present study, we use geometries constructed from longitudinal CT images obtained during AAA follow-up studies and investigate relations between multiple hemodynamics factors with local expansion of AAAs.

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

Journal of Biomechanical Engineering ◽

10.1115/1.1894180 ◽

2005 ◽

Vol 127 (3) ◽

pp. 374-382 ◽

Cited By ~ 36

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.

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RECAPITULATING THE VASCULAR MICROENVIRONMENT IN MICROFLUIDIC PLATFORMS

Nano LIFE ◽

10.1142/s1793984413400011 ◽

2013 ◽

Vol 03 (01) ◽

pp. 1340001 ◽

Cited By ~ 11

Author(s):

HASAN E. ABACI ◽

GERMAN DRAZER ◽

SHARON GERECHT

Keyword(s):

Shear Stress ◽

Oxygen Tension ◽

Vascular Diseases ◽

Microfluidic Devices ◽

Cyclic Stretch ◽

Microfluidic Platforms ◽

Microfluidic Technology ◽

Mechanical Factors ◽

Micro Systems

The vasculature is regulated by various chemical and mechanical factors. Reproducing these factors in vitro is crucial for the understanding of the mechanisms underlying vascular diseases and the development of new therapeutics and delivery techniques. Microfluidic technology offers opportunities to precisely control the level, duration and extent of various cues, providing unprecedented capabilities to recapitulate the vascular microenvironment. In the first part of this article, we review existing microfluidic technology that is capable of controlling both chemical and mechanical factors regulating the vascular microenvironment. In particular, we focus on micro-systems developed for controlling key parameters such as oxygen tension, co-culture, shear stress, cyclic stretch and flow patterns. In the second part of this article, we highlight recent advances that resulted from the use of these microfluidic devices for vascular research.

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A Dielectrophoretic Device for Studying Single Cell Mechanics

ASME 2009 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2009-206845 ◽

2009 ◽

Author(s):

Kavitha Rajendran ◽

Greeshma Manomohan ◽

Alisa Morss Clyne

Keyword(s):

Endothelial Cells ◽

Shear Stress ◽

Cell Mechanics ◽

Fluid Shear Stress ◽

Cell Function ◽

Vascular Diseases ◽

Cyclic Stretch ◽

Fluid Shear ◽

Mechanical Environment ◽

Pathological Conditions

Mechanics plays an important role in cell function, both in normal physiology and pathological conditions. In the vasculature, the endothelial cells that line blood vessels dynamically respond to the mechanical environment. Endothelial cells sense both fluid shear stress and cyclic stretch, and alterations in these forces may contribute to vascular diseases such as atherosclerosis.

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Fluid-Induced Shear Stress Stimulates Ca2+ Signaling in Human Tendon Epitenon Cells

10.1115/imece1999-0401 ◽

1999 ◽

Author(s):

Eric Francke ◽

Michelle K. Elfervig ◽

Ajay Sood ◽

Thomas D. Brown ◽

Donald K. Bynum ◽

...

Keyword(s):

Shear Stress ◽

Cultured Cells ◽

Vascular System ◽

Ex Vivo ◽

Cyclic Stretch ◽

Shear Stresses ◽

Mechanical Stimuli ◽

Transient Rise ◽

Tendon Cells ◽

Substrate Stretching

Abstract Tendon cells reside in an environment rich in mechanical stimuli and respond to these stimuli with a variety of activities. Whole tendon, ex vivo, responds to cyclic stretch by increasing DNA and collagen synthesis (Banes et al., 1999). Cultured epitenon and internal cells from tendon respond synergistically to cyclic tensile strain and a growth factor (Banes et al., 1995). Tendon cells stimulated by plasma membrane indentation with a micropipet propagate intercellular calcium waves to neighboring cells via gap junctions (Kenamond et al., 1997). Tendon cells subjected to equibiaxial cyclic stretching signal with a transient rise in intracellular calcium (Kenamond et al., 1998). Recently, it has been shown that connective tissue cells are responsive to fluid-induced shear stress similar to cells of the vascular system. Moreover, Brown and coworkers have shown that apparati used to apply substrate tension to cultured cells have limitations that include a potentially confounding component of fluid-induced shear stress (Brown et al., 1998). Hence, there is a concern that a given cell response to substrate stretching may actually involve a response to shear stress or some combination of the two stimuli. We have designed a parallel plate, laminar flow apparatus that provides regulated fluid-induced shear stress and subjected tendon cells to shear stresses of 0, 5, 10, 15 and 20 dynes/cm2. This will enable us to make a direct comparison between fluid-induced shear stress and substrate deformation on tendon cell signaling and downstream gene responses.

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

International Journal of Scientific Reports ◽

10.18203/issn.2454-2156.intjscirep20212391 ◽

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

Background: 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.Methods: 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. Results: 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.Conclusions: 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.

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