Spatial Relationships in Early Signaling Events of Flow-Mediated Endothelial Mechanotransduction

Davies, Peter F.; Barbee, Kenneth A.; Volin, Michael V.; Robotewskyj, Andre; Chen, Jai; Joseph, Loren; Griem, Melvin L.; Wernick, Miles N.; Jacobs, Elizabeth R.; Polacek, Denise C.; DePaola, Natacha; Barakat, Abdul I.

doi:10.1146/annurev.physiol.59.1.527

Cited by 293 publications

(204 citation statements)

References 84 publications

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“…VEGF has a central role in regulating vascular permeability and angiogenesis (Ferrara et al, 2003), and thus an understanding of its ability to regulate the cadherin-and integrin-based adhesion systems is an important avenue of study. Nonetheless, our data implicate a critical role for VE-cadherin signaling through RhoA to affect cell shape and focal adhesions, and they support the growing body of evidence suggesting that cell-cell and cell-matrix adhesion are mechanically coupled in endothelial cells (Davies et al, 1997;Dudek and Garcia, 2001). Many inflammatory agents that are known to induce permeability by disrupting junctional VEcadherin, including peroxide and histamine, may mediate part of their effects indirectly through the cadherin-mediated changes in cell-matrix adhesion (Alexander and Elrod, 2002).…”

Section: Discussionsupporting

confidence: 82%

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Vascular Endothelial-Cadherin Regulates Cytoskeletal Tension, Cell Spreading, and Focal Adhesions by Stimulating RhoA

Nelson

Pirone

Tan

et al. 2004

MBoC

166

137

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Changes in vascular endothelial (VE)-cadherin-mediated cell-cell adhesion and integrin-mediated cell-matrix adhesion coordinate to affect the physical and mechanical rearrangements of the endothelium, although the mechanisms for such cross talk remain undefined. Herein, we describe the regulation of focal adhesion formation and cytoskeletal tension by intercellular VE-cadherin engagement, and the molecular mechanism by which this occurs. Increasing the density of endothelial cells to increase cell-cell contact decreased focal adhesions by decreasing cell spreading. This contact inhibition of cell spreading was blocked by disrupting VE-cadherin engagement with an adenovirus encoding dominant negative VE-cadherin. When changes in cell spreading were prevented by culturing cells on a micropatterned substrate, VE-cadherin-mediated cell-cell contact paradoxically increased focal adhesion formation. We show that VE-cadherin engagement mediates each of these effects by inducing both a transient and sustained activation of RhoA. Both the increase and decrease in cell-matrix adhesion were blocked by disrupting intracellular tension and signaling through the Rho-ROCK pathway. In all, these findings demonstrate that VE-cadherin signals through RhoA and the actin cytoskeleton to cross talk with cell-matrix adhesion and thereby define a novel pathway by which cell-cell contact alters the global mechanical and functional state of cells. INTRODUCTIONCoordinated changes between cell adhesion to the extracellular matrix (ECM) and to neighboring cells are crucial for the many physical transformations that cells must undergo during development, tissue homeostasis, and wound healing. In the endothelium, where a single layer of cells separates tissues from their blood supply, the concerted regulation of cell-cell and cell-ECM adhesion drives rapid changes in cell shape and vascular architecture essential to vascular remodeling in both normal and disease processes (Vestweber, 2000;Dudek and Garcia, 2001). Dynamic changes in cell-cell and cell-matrix adhesion and mechanical forces are responsible for regulating vascular permeability, and agents that alter permeability invariably affect both types of adhesion complexes (Dudek and Garcia, 2001). During blood vessel sprouting and migration in angiogenesis, endothelial cells must disassemble and reform their cell-cell and cell-ECM contacts in synchrony to generate appropriate structures. These two adhesion systems each regulate their functional effects through both biochemical and mechanical signals.Changes in integrin binding to ECM not only alter signals that regulate cell proliferation, migration, and survival (Assoian and Schwartz, 2001;Hood and Cheresh, 2002;Stupack and Cheresh, 2002) but also modulate cell mechanics by affecting focal adhesion (FA) maturation, adhesion strength, cytoskeletal contractility, and cell shape (Geiger and Bershadsky, 2002;Juliano, 2002). Likewise, changes in the engagement of vascular endothelial (VE)-cadherin, the principal junctional molecule in endothe...

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Section: Discussionsupporting

confidence: 82%

“…junctions can be transmitted through the actin cytoskeleton directly to FAs (Davies et al, 1997;Ko et al, 2001;Shay-Salit et al, 2002). Because FAs are sensitive to such forces, changes in VE-cadherin binding likely alter FA formation mechanically ).…”

Section: Introductionmentioning

confidence: 99%

Vascular Endothelial-Cadherin Regulates Cytoskeletal Tension, Cell Spreading, and Focal Adhesions by Stimulating RhoA

Nelson

Pirone

Tan

et al. 2004

MBoC

166

137

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“…Transcription and synthesis of nuclear factors such as early growth response-1 (EGR-1) that can transactivate a specific ECM gene are considered secondary responses to mechanical loads (Schwachtgen et al, 1998;. Finally, mechanisms that include triggering autocrine or paracrine release of growth factors such as TGF-β by mechanical loads to regulate the transcription of "mechanoresponsive genes" are also presented (Davies et al, 1997;Sadoshima and Izumo, 1997). Mechanical stress stimulates the release of TGF-β (Lindahl et al, 2002;Nakatani et al, 2002;Yang et al, 2004) as described in the previous section, as well as enhances its gene transcription through activation of EGR-1 .…”

Section: Cellular Mechanotransductionmentioning

confidence: 99%

Mechanoregulation of gene expression in fibroblasts

Wang

Thampatty

Lin

et al. 2007

Gene

227

187

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Mechanical loads placed on connective tissues alter gene expression in fibroblasts through mechanotransduction mechanisms by which cells convert mechanical signals into cellular biological events, such as gene expression of extracellular matrix components (e.g., collagen). This mechanical regulation of ECM gene expression affords maintenance of connective tissue homeostasis. However, mechanical loads can also interfere with homeostatic cellular gene expression and consequently cause the pathogenesis of connective tissue diseases such as tendinopathy and osteoarthritis. Therefore, the regulation of gene expression by mechanical loads is closely related to connective tissue physiology and pathology. This article reviews the effects of various mechanical loading conditions on gene regulation in fibroblasts and discusses several mechanotransduction mechanisms. Future research directions in mechanoregulation of gene expression are also suggested.

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“…The levels of two other immediate-early genes, fosb and c-jun, also increased transiently after fibroblast contraction, whereas the levels of fra-1, fra-2, c-myc, and the transcription factor NF-B remained the same, indicating that fibroblast contraction caused changes in a selective group of genes. The increase in c-fos mRNA during contraction of stressed collagen matrices may reflect a unique role for c-fos in mechanoregulated events at the end of wound repair.Mechanical force influences cell function in animal and plant tissues (6,11,30,67). For instance, increased mechanical load, such as fluid flow over endothelial cells or tension applied to muscle cells, has been shown to result in cell proliferation or hypertrophy (15, 64).…”

mentioning

confidence: 99%

Increased c-fos mRNA Expression By Human Fibroblasts Contracting Stressed Collagen Matrices

Rosenfeldt

Lee

Grinnell

1998

Molecular and Cellular Biology

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We studied early changes in gene expression during fibroblast contraction of stressed collagen matrices. The level of c-fos mRNA increased dramatically and peaked 50 to 60 min after matrix contraction was initiated. This response did not require serum and could not be accounted for simply by disruption of the actin cytoskeleton. Increased c-fos mRNA levels required Ca 2؉ influx but not the cyclic AMP or extracellular signal-regulated kinase (ERK 1/2) signaling pathways, both of which are activated when fibroblasts contract stressed collagen matrices. The levels of two other immediate-early genes, fosb and c-jun, also increased transiently after fibroblast contraction, whereas the levels of fra-1, fra-2, c-myc, and the transcription factor NF-B remained the same, indicating that fibroblast contraction caused changes in a selective group of genes. The increase in c-fos mRNA during contraction of stressed collagen matrices may reflect a unique role for c-fos in mechanoregulated events at the end of wound repair.Mechanical force influences cell function in animal and plant tissues (6,11,30,67). For instance, increased mechanical load, such as fluid flow over endothelial cells or tension applied to muscle cells, has been shown to result in cell proliferation or hypertrophy (15, 64). During wound repair, mechanical force within the wound tissue pulls the wound edges closer together, which in pathological cases results in scarring and loss of function (29, 52). Wound contraction is believed to be mediated by fibroblasts as they go through a cycle of migration, proliferation, contraction, and regression (13,40).Fibroblasts cultured in collagen matrices have been used as an in vitro model for wound contraction (3,20). In this model, cells reorganize the extracellular matrix through migratory and contractile activities (3, 25), resulting in formation of a dense, tissue-like structure. The fibroblast phenotype that develops during collagen matrix reorganization differs dramatically depending upon whether collagen matrices are floating in medium or attached to a rigid support. After reorganization of attached matrices, the cells resemble proliferating fibroblasts of wound tissue under mechanical stress and are characterized by polarized morphology, prominent stress fibers, and fibronexus junctions (23,37,45,62). Cells in attached collagen matrices exert force on the matrix similar to that observed in contracting skin wounds (12, 34). After reorganization of floating matrices, on the other hand, cells resemble nondividing fibroblasts of resting dermis or scar tissue in a state of mechanical equilibrium and are characterized by isometric (stellate) cell morphology and cytoskeletal meshwork (3, 4).We have combined the attached and floating models to study the regulatory events associated with the transition of fibroblasts from mechanically stressed to mechanically equilibrated conditions (stress-relaxation) such as occurs by the end of wound repair. Initially, fibroblasts are cultured in attached collagen matrices until mechan...

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Spatial Relationships in Early Signaling Events of Flow-Mediated Endothelial Mechanotransduction

Cited by 293 publications

References 84 publications

Vascular Endothelial-Cadherin Regulates Cytoskeletal Tension, Cell Spreading, and Focal Adhesions by Stimulating RhoA

Vascular Endothelial-Cadherin Regulates Cytoskeletal Tension, Cell Spreading, and Focal Adhesions by Stimulating RhoA

Mechanoregulation of gene expression in fibroblasts

Increased c-fos mRNA Expression By Human Fibroblasts Contracting Stressed Collagen Matrices

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