Cadherins Mediate Intercellular Mechanical Signaling in Fibroblasts by Activation of Stretch-sensitive Calcium-permeable Channels

Cells in mechanically active environments form extensive, cadherin-mediated intercellular junctions that are important in tissue remodeling and differentiation. Currently, it is unknown whether adherens junctions in connective tissue fibroblasts transmit mechanical signals and coordinate multicellular adaptations to physical forces. We hypothesized that cadherins mediate intercellular mechanotransduction by activating calcium-permeable, stretch-sensitive channels. Human gingival fibroblasts in suspension were plated on established homotypic monolayer cultures. The cells formed intercellular adherens junctions. Controlled mechanical forces were applied to intercellular junctions by electromagnets acting on cells containing internalized magnetite beads. At early but not later stages of intercellular attachment, force application visibly displaced magnetite bead-loaded cells and induced robust Ca2+transients (65 ± 9.4 nm above base line). Similar Ca2+ transients were induced by force application to anti-N-cadherin antibody-coated magnetite beads. Ca2+responses depended on influx of extracellular Ca2+ through mechanosensitive channels because both Ca2+ chelation and gadolinium chloride abolished the response and MnCl2quenched fura-2 fluorescence after force application. Force application induced accumulation of microinjected rhodamine-actin at intercellular contacts; actin assembly was inhibited by buffering intracellular calcium fluxes. Our results indicate that mechanical forces applied to adherens junctions activate stretch-sensitive calcium-permeable channels and increase actin polymerization. We suggest that N-cadherins in fibroblasts are intercellular mechanotransducers. Cells in mechanically active environments form extensive, cadherin-mediated intercellular junctions that are important in tissue remodeling and differentiation. Currently, it is unknown whether adherens junctions in connective tissue fibroblasts transmit mechanical signals and coordinate multicellular adaptations to physical forces. We hypothesized that cadherins mediate intercellular mechanotransduction by activating calcium-permeable, stretch-sensitive channels. Human gingival fibroblasts in suspension were plated on established homotypic monolayer cultures. The cells formed intercellular adherens junctions. Controlled mechanical forces were applied to intercellular junctions by electromagnets acting on cells containing internalized magnetite beads. At early but not later stages of intercellular attachment, force application visibly displaced magnetite bead-loaded cells and induced robust Ca2+transients (65 ± 9.4 nm above base line). Similar Ca2+ transients were induced by force application to anti-N-cadherin antibody-coated magnetite beads. Ca2+responses depended on influx of extracellular Ca2+ through mechanosensitive channels because both Ca2+ chelation and gadolinium chloride abolished the response and MnCl2quenched fura-2 fluorescence after force application. Force application induced accumulation of microinjected rhodamine-actin at intercellular contacts; actin assembly was inhibited by buffering intracellular calcium fluxes. Our results indicate that mechanical forces applied to adherens junctions activate stretch-sensitive calcium-permeable channels and increase actin polymerization. We suggest that N-cadherins in fibroblasts are intercellular mechanotransducers. newton fluorescein isothiocyanate [1,2-bis(o-amino-5-bromophenoxy)ethane-N,N,N′,N′-tetraacetic, 4Na] mag-fura2 α-minimal essential medium phosphate-buffered saline suspended cells substrate-attached cells endoplasmic reticulum Intercellular junctions are dynamic structures essential for the maintenance of tissue integrity (1Takeichi M. Curr. Opin. Cell Biol. 1995; 7: 619-627Crossref PubMed Scopus (1262) Google Scholar) and tissue repair after injury (2Gabbiani G Rungger-Brandle E. Glynn L.E. Tissue Repair and Regeneration: Handbook of Inflammation. 3. Elsevier Science Publishers B.V., Amsterdam1981: 1-50Google Scholar), for coordination of tissue remodeling responses to physiological forces (3Xu J Liu M. Tanswell A.K. Post M. Am. J. Physiol. 1998; 275: L545-L550PubMed Google Scholar), and for elaboration of protective adaptations as a result of pathological forces (4Wang X. Gerdes A.M. J. Mol. Cell. Cardiol. 1999; 31: 333-343Abstract Full Text PDF PubMed Scopus (90) Google Scholar). In wound healing, intercellular contacts involving interactions between cadherins, actin, and myosin have been implicated in generating the forces required for wound closure (5Adams C.L. Nelson W.J. Curr. Opin. Cell Biol. 1998; 10: 572-577Crossref PubMed Scopus (238) Google Scholar). Notably, maintenance of the structure of intercellular contacts critically depends upon contractile forces generated by the actin cytoskeleton (6Gloushankova N.A Krendel M.F. Alieva N.O. Bonder E.M. Feder H.H. Vasiliev J.M. Gelfand I.M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 4362-4367Crossref PubMed Scopus (70) Google Scholar) that act on intercellular contacts in adjacent cells (7Danjo Y. Gipson I.K. J. Cell Sci. 1998; 111: 3323-3332PubMed Google Scholar). Collectively, these data suggest that force application to intercellular junctions is of central importance in tissue homeostasis, but the specific role of intercellular junctional proteins in transducing physical forces into regulatory signals is poorly understood. Tension transmitted through adherens junctions can change the viscoelastic properties of fibroblasts (8Ragsdale G.K. Phelps J. Luby-Phelps K. Biophys. J. 1997; 73: 2798-2808Abstract Full Text PDF PubMed Google Scholar) and may initiate intercellular mechanotransduction via calcium wave propagation through gap junctions (9Boitano S. Sanderson M.J. Dirksen E.R. J. Cell Sci. 1994; 107: 3037-3044PubMed Google Scholar, 10Hansen M. Boitano S. Dirksen E.R. Sanderson M.J. J. Cell Sci. 1996; 108: 2583-2590Google Scholar, 11Xia S.L. Ferrier J. Biochem. Biophys. Res. Commun. 1992; 186: 1212-1219Crossref PubMed Scopus (102) Google Scholar). However, mechanotransduction through intercellular adherens junctions of connective tissue cells has not been examined in detail. Consequently the mechanisms of force-sensing and signal transduction at intercellular junctions remain largely unknown. Studies of biomechanical stimulation to intercellular junctions have typically used fluid flow stress or stretching of deformable substrates to apply forces to confluent cell monolayers. For example, endothelial cells exhibit profound changes in cell shape in response to altered shear stress, and these responses require reorganization of intercellular adherens junctions (12Noria S. Cowan D.B. Gotlieb A.I. Langille B.L. Circ. Res. 1999; 85: 504-514Crossref PubMed Scopus (199) Google Scholar). However, it is not clear whether the morphological changes of intercellular junctions observed in these and related experiments were a direct result of force application to the junctions or were secondary to alterations in cell-substratum adhesions. Further, the nature of the signals that are generated as a result of direct mechanical stimulation of intercellular adhesions remains elusive. To test whether intercellular adhesion complexes can transmit mechanical signals, we developed and characterized a novel model system that delivers controlled physical forces (∼30–150 pN)1 to intercellular junctions, and we measured [Ca2+]i when these junctions were stretched. We used fibroblasts from periodontal connective tissues because these cells form extensive intercellular adherens and gap junctions in vivo (13Beertsen W. Everts V. J. Periodont. Res. 1980; 16: 524-541Crossref Scopus (10) Google Scholar, 14Shore R.C. Berkovitz B.K.B. Moxham B. J. Anat. 1981; 133: 67-76PubMed Google Scholar) and in vitro (15Ko K. Arora P. Lee W. McCulloch C. Am. J. Physiol. 2000; 279: C147-C157Crossref PubMed Google Scholar). Further, periodontal cells are subjected constitutively to high amplitude mechanical loads in vivo. With the use of specific gap junction inhibitors and anti-cadherin antibody-coated magnetic beads, we delineated the role of cadherin-mediated adherens junctions in intercellular mechanotransduction. Our major finding is that mechanical forces applied to intercellular junctions induce robust intracellular calcium transients of gap junctions. To the of is the that forces transmitted through cadherins can activate a system and induce actin at force application proteins anti-N-cadherin adhesion and magnetite beads, gadolinium and were from and were from actin was from magnetic were from was from and were by the Human gingival fibroblasts were from as McCulloch J. Cell Sci. PubMed Google Scholar). The cells from were as in Full medium of α-minimal essential medium G in and The cells were to to experiments when were used as To and specific in was for cadherins and Cells on were and at for in for and for at containing and was on a and secondary was used to and proteins at the intercellular between suspended and substrate-attached cells as K. Arora P. V. A. McCulloch C. J. Cell Sci. PubMed Google Scholar). For was at and was a nm The cells were a and were from the of cell at the of the cell to the of the cell by The was to at the between the cells and by of the of the of the and cells For of cell intracellular calcium the cells on were at for For of calcium the cells were A.M. B. S. J. 1998; PubMed Scopus Google Scholar) for at in containing 1997; 275: PubMed Scopus Google Scholar). The is of and of For experiments was to the The cells on were and to a tissue of cells by fluorescence of that the of of cells of intracellular cell [Ca2+]i were a to a and system The fura-2 or were at of and nm from at fluorescence was a and through a nm was used to to of [Ca2+]i of the intracellular of fura-2 were from fluorescence to the of M. J. Biol. Full Text PDF PubMed Scopus Google Scholar) and as K. M. McCulloch 1998; PubMed Google Scholar). of cells and cells were measured in were to a a at were in and in of was in of to a of For of cells internalized beads, containing of were a confluent cell on a tissue that the was The cell was phosphate-buffered saline to or beads. cells were to on the of the and in M. McCulloch Cell Tissue Res. PubMed Scopus Google Scholar, M. J. McCulloch J. Cell Sci. PubMed Google Scholar) have that but not internalized beads. of was by and of cells at for The of cells was by flow as W. J. McCulloch J. Cell. Physiol. 1996; PubMed Scopus Google Scholar), and ± of cells were to To the of cells internalized were and for to and were on the of cells by internalized ± a cell of To test the of we used magnetic that were anti-N-cadherin or magnetic to were or at a of of in for at were and monolayer of cells for at in to to the cell were by Force was generated on of as M. Ferrier J. McCulloch Am. J. Physiol. 1995; PubMed Google Scholar). was from a of The was wound of direct was used that and was that a from the to the cell was through the of a of ± G a of the force application was used for experiments in a force stretching the intercellular junctions between cells and In experiments anti-N-cadherin beads, force was applied to the cadherin-mediated In a was used to forces M. Ferrier J. J. Physiol. 1998; PubMed Scopus Google Scholar) on cells internalized to the of For these experiments the was and from the cell The force generated by magnetic application to a cell internalized was of Scholar) and from direct of the of these cells in of as M. Ferrier J. McCulloch Am. J. Physiol. 1995; PubMed Google Scholar). To applied we cells high of cell and applied a of at to the We that because cells are to cells largely through cadherin-mediated adherens junctions (15Ko K. Arora P. Lee W. McCulloch C. Am. J. Physiol. 2000; 279: C147-C157Crossref PubMed Google Scholar), the forces applied to the cells are to these junctions. the above M. Ferrier J. McCulloch Am. J. Physiol. 1995; PubMed Google Scholar), we that the force applied to these intercellular contacts is ± cell was used to whether and force application to the cells the of the were as W. J. McCulloch J. Cell. Physiol. 1996; PubMed Scopus Google Scholar). of by the cells and force the cells were at and in to a cell of The cells were by flow The cells for were to in The for were from and on a For the cells were a a were model and model actin for was in and for were for at to and were of cell For the and were and when between were the at of was by by a test the at We developed a model to test whether adherens junctions are by controlled mechanical forces through cells internalized Human fibroblasts were for by M. McCulloch Cell Tissue Res. PubMed Scopus Google Scholar). of these cells of the on transmitted the of via was to tissue of confluent cells Notably, not increase We the of the cell by to ± by of cells internalized beads. was the by transmitted The cells internalized were suspended by in the of calcium to and were substrate-attached of We have that cells and cells form intercellular adherens junctions (15Ko K. Arora P. Lee W. McCulloch C. Am. J. Physiol. 2000; 279: C147-C157Crossref PubMed Google Scholar) that are cadherin-mediated K. Arora P. V. A. McCulloch C. J. Cell Sci. PubMed Google Scholar). of ± was the cells were the of the and but were not because cells are to cells through adherens junctions (15Ko K. Arora P. Lee W. McCulloch C. Am. J. Physiol. 2000; 279: C147-C157Crossref PubMed Google Scholar). The mechanical force applied to the intercellular junctions was by of cells internalized through and was for cells high cells are to generated force is applied to the intercellular junctions between the cell and of the cell when the magnetic force was applied we that the increase in may activate mechanosensitive channels Physiol. 1995; PubMed Scopus Google To model of intercellular we whether fibroblasts internalized are and exhibit or force application. At the of these cells and as by to to cells or to a cell Further, of cells as when for the of cells by flow Force application to cells internalized not because to a was the as that of The fluorescence of the of cells internalized ± fluorescence and the internalized and force ± was not from cells ± on a and cell McCulloch J. Cell Sci. 1994; 107: PubMed Google Scholar) in between and bead-loaded cells ± of of and the that force application not change the of these that was We whether forces applied to intercellular adherens junctions activate intracellular calcium on the periodontal model used that intercellular adhesion is on cadherin-mediated adherens junctions K. Arora P. V. A. McCulloch C. J. Cell Sci. PubMed Google Scholar). magnetic force application to bead-loaded cells that were to substrate-attached we observed robust [Ca2+]i in cells but not in cells The from force application to [Ca2+]i increase between and We whether of the cell induce a calcium by [Ca2+]i in substrate-attached cells internalized magnetic force application. In these change of [Ca2+]i was observed that [Ca2+]i were specific to stretching of intercellular junctions and not to from intracellular We that the [Ca2+]i responses to intercellular stretching as contacts at early stages of intercellular attachment, force application visibly displaced magnetite suspended cells and induced robust Ca2+ transients (65 ± 9.4 nm above base in substrate-attached cells response as intercellular junctions to stretching a of (15Ko K. Arora P. Lee W. McCulloch C. Am. J. Physiol. 2000; 279: C147-C157Crossref PubMed Google Scholar) when the applied force of induce The response to the intercellular We measured the of and at the intercellular by and the that intercellular in Ca2+responses after may a reorganization of intercellular We the of Ca2+ for the observed in To whether the increase of [Ca2+]i after force application was to Ca2+ influx or of cells were to a containing force application. these force application to induce a Ca2+ that the robust intracellular Ca2+ response was at in on calcium influx through channels. a of cells mechanosensitive channels Physiol. 1995; PubMed Scopus Google Scholar) that mediate the influx of the in response to we examined whether mechanosensitive channels a role in intercellular We the stretching experiments in the of that mechanosensitive channels in PubMed Scopus Google Scholar) and in periodontal fibroblasts M. Ferrier J. McCulloch Am. J. Physiol. 1995; PubMed Google Scholar). of the cells to intercellular stretching that mechanosensitive channels may important role in the of mechanosensitive channels to cells and fura-2 J. Physiol. PubMed Scopus Google Scholar). In the of we observed a in fluorescence after application of magnetic force by influx of and of fura-2 fluorescence when measured at the In the of was change in fura-2 fluorescence that was because of Collectively, these results indicate that stretching cells at intercellular junctions Ca2+transients as a result of calcium through mechanosensitive channels. To test whether Ca2+ is from in response to stretching of intercellular junctions, the cells were A.M. B. S. J. 1998; PubMed Scopus Google Scholar). of these cells that the was in to the Force applied to the intercellular junctions change in the of to these cells induced a of the by a to base because of calcium from the in these cells are 1997; 275: PubMed Scopus Google Scholar). data that the [Ca2+]i increase in response to stretching is to calcium through mechanosensitive channels but is not on of Intercellular mechanotransduction via calcium wave propagation through gap junctions has been in cells (9Boitano S. Sanderson M.J. Dirksen E.R. J. Cell Sci. 1994; 107: 3037-3044PubMed Google Scholar, 10Hansen M. Boitano S. Dirksen E.R. Sanderson M.J. J. Cell Sci. 1996; 108: 2583-2590Google Scholar) and in cells S.L. Ferrier J. Biochem. Biophys. Res. Commun. 1992; 186: 1212-1219Crossref PubMed Scopus (102) Google Scholar). We the that the intercellular [Ca2+]i response to of from the cells to cells through gap junctions and not to the stretching of adherens junctions. We cell in the of inhibitors of gap junctional I.M. Biochem. Res. Commun. PubMed Scopus Google S. Sci. 1998; Google Scholar) and the of these have been to inhibitors of gap in fibroblasts (15Ko K. Arora P. Lee W. McCulloch C. Am. J. Physiol. 2000; 279: C147-C157Crossref PubMed Google Scholar). a that gap junction and X. S. Mol. 1996; 16: PubMed Scopus Google Scholar), not the intercellular [Ca2+]i response ± nm above base of gap junctional was by has the as a of the extracellular of the gap junction in gingival fibroblasts (15Ko K. Arora P. Lee W. McCulloch C. Am. J. Physiol. 2000; 279: C147-C157Crossref PubMed Google Scholar). by interactions and integrity J. Physiol. 1997; Scopus Google Biochem. Res. Commun. 1999; PubMed Scopus Google Scholar) but not intercellular [Ca2+]i response to ± nm above base results suggest that gap junctions are not in the of intercellular We characterized the specific for intercellular of mechanosensitive channels. In confluent but not as by flow that of cell is by the of intercellular The cells were antibody-coated and subjected to have that anti-cadherin antibody-coated to cells through adherens structures S. B. J. Cell Sci. 1998; 111: Google Scholar). magnetic force was applied to that were to the of confluent we observed robust [Ca2+]i transients to that from stretching intercellular junctions from force application to of magnetic to cells antibody-coated to [Ca2+]i responses because was Further, we were not to Ca2+ responses from cells in because on the cell was not for the of these responses to to stretching of the cell of cadherins, we to the not actin The gingival fibroblasts cell and to to the cells However, antibody-coated calcium response after force application Collectively, these data indicate that the stretching response was in cadherin-mediated and was not to stretching of actin [Ca2+]i the assembly and of actin Physiol. 1994; PubMed Scopus Google Scholar), in are major of intercellular junctions, we examined the that [Ca2+]i transients generated from stretching intercellular junctions actin polymerization. We cell in cells were microinjected The microinjected actin were as by into stress after at for force was applied to cells and intercellular junctions were for we observed actin assembly at of intercellular contacts of actin is that actin stress in response to contractile stress transmitted through adherens junctions in fibroblasts (8Ragsdale G.K. Phelps J. Luby-Phelps K. Biophys. J. 1997; 73: 2798-2808Abstract Full Text PDF PubMed Google Scholar). To the of cell actin, we the of cell established intercellular junctions of K. Arora P. V. A. McCulloch C. J. Cell Sci. PubMed Google Scholar) or force application and and cadherins We that force application by as measured by of ± ± the of and cadherins to the was To test whether actin was on we intracellular calcium transients by the cell to stretching these force application not changes in for actin that [Ca2+]i is required for actin To mechanical signals are transmitted from cell to cell and multicellular responses to mechanical forces are we have developed a novel model system in magnetic forces are applied to intercellular junctions in cells containing internalized magnetite beads. intercellular junctions are in endothelial and have been in We used periodontal fibroblasts in model because form of that are largely cadherin-mediated K. Arora P. V. A. McCulloch C. J. Cell Sci. PubMed Google Scholar). In intercellular junctions in cells structures as junctions, adherens junctions, and that the of intercellular mechanotransduction. Our system the of direct and specific stretching forces to the intercellular adherens junctions of The of a novel was required to of used that apply forces to confluent cell fluid flow or stretching of that of both and adhesion Our model has the model forces to intercellular adherens junctions. fibroblasts exhibit high of M. J. McCulloch J. Cell Sci. PubMed Google Scholar) of beads. it has been to high of magnetite into cells and high forces to calcium in the stretching it is not to the forces applied to intercellular junctions because the but not the stress is In we were to the of forces applied to the intercellular junctions by the of cells internalized in Further, the of applied forces can controlled by the of the magnetic we were to apply forces of or to intercellular intercellular contacts are to these forces because the cell application of forces stress on endothelial cells have used forces from to of cells from the substrates at J. and the Cell. Scholar). Similar force were used in cadherin-mediated contacts in cell not when to shear forces in of C.L. B. A.M. A. J. Cell Sci. 1995; 108: PubMed Google Scholar). The forces we applied of cell are in to forces generated by the forces on the of fibroblasts are to Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). We have that and stretching of these cells not the cell at force of and that cells exhibit as measured by of and the We have that when force is applied to intercellular junctions, was of cells on We have that the between cells and cells are largely cadherin-mediated K. Arora P. V. A. McCulloch C. J. Cell Sci. PubMed Google Scholar). Our data that stretching forces applied through these contacts induce calcium transients that to base Notably, cells but not cells calcium responses to stretching at intercellular junctions. cells are and cells are these are results that cell shape is in of responses to McCulloch J. Cell. Physiol. 1994; PubMed Scopus Google Scholar). The of calcium signal in the cells was not to fluorescence of fura-2 by the internalized magnetite because we were to and signals to calcium We suggest that the of response in the cells is to the of actin in these cells and to transmit forces from the cadherin-mediated intercellular junctions to mechanosensitive channels. The [Ca2+]i response was when cells were in or in the of the gadolinium chloride PubMed Scopus Google Scholar), that calcium influx through channels is the of the [Ca2+]i of channels after stretching is by of fura-2 fluorescence in the of We suggest that forces transmitted through adherens junctions changes in to of the of mechanosensitive channels Physiol. 1995; PubMed Scopus Google Scholar) and the of mechanical signals may through specific P. B. Cell Biol. 2000; PubMed Scopus Google Scholar), we hypothesized that of channels intercellular stretching is through adherens junctions. applied through via can activate mechanosensitive channels M. Ferrier J. McCulloch Am. J. Physiol. 1995; PubMed Google Scholar). we have that forces applied to cadherin-mediated adherens junctions via anti-N-cadherin antibody-coated S. B. J. Cell Sci. 1998; 111: Google Scholar) can induce [Ca2+]i responses as by stretching of the cell we that the [Ca2+]i response amplitude was related to the of on the cell that a of is required for of mechanotransduction. However, we by intercellular adhesion In stretching experiments to the we of calcium results suggest that cadherin-mediated adherens junctions are intercellular of the of channels and that to actin may a finding was that the amplitude of calcium transients as the of intercellular that the calcium transients that are by stretching are related to the force generated by magnetic in and the of cadherin-mediated intercellular We that as cadherin-mediated junctions are formed by the of the force applied to cadherin-mediated junction as the is in calcium We that the [Ca2+]i responses have been through gap junctions (9Boitano S. Sanderson M.J. Dirksen E.R. J. Cell Sci. 1994; 107: 3037-3044PubMed Google Scholar, 10Hansen M. Boitano S. Dirksen E.R. Sanderson M.J. J. Cell Sci. 1996; 108: 2583-2590Google Scholar, 11Xia S.L. Ferrier J. Biochem. Biophys. Res. Commun. 1992; 186: 1212-1219Crossref PubMed Scopus (102) Google Scholar) because periodontal fibroblasts can form extensive gap junctions in vitro (15Ko K. Arora P. Lee W. McCulloch C. Am. J. Physiol. 2000; 279: C147-C157Crossref PubMed Google Scholar). We that cells but not cells calcium transients in response to that intercellular flow of through gap junctions from to cells was not Further, of cells inhibitors of gap junctions, as and not the [Ca2+]i response in that gap junctional is not required for of We have the importance of actin in the and maintenance of intercellular junctions in fibroblasts K. Arora P. V. A. McCulloch C. J. Cell Sci. PubMed Google Scholar), and in we that actin assembly is by cadherin-mediated mechanotransduction In cells microinjected actin stretching of intercellular junctions induced accumulation of actin adjacent to force application finding is in in actin actin to cells via coordinate wound closure J. K. J. P. J. Cell Biol. 1996; PubMed Scopus Google Scholar). has been that the for actin reorganization at the wound is a change in the of in the a signal J. K. J. P. J. Cell Biol. 1996; PubMed Scopus Google Scholar). is by the that can and force in the of adherens junctions as a result of actin reorganization Am. J Physiol. 1999; Scholar). In model the accumulation of actin was abolished by intracellular buffering of calcium that actin reorganization is through the intracellular calcium signals by when the intercellular junctions are stretched. In to (1Takeichi M. Curr. Opin. Cell Biol. 1995; 7: 619-627Crossref PubMed Scopus (1262) Google Scholar), we suggest that cadherin-mediated adherens junctions a role in mechanotransduction in multicellular junctions are important in coordination of wound closure in connective tissue cells in vivo (2Gabbiani G Rungger-Brandle E. Glynn L.E. Tissue Repair and Regeneration: Handbook of Inflammation. 3. Elsevier Science Publishers B.V., Amsterdam1981: 1-50Google Scholar), and have that maintenance of intercellular contacts depends on the of the actin cytoskeleton (6Gloushankova N.A Krendel M.F. Alieva N.O. Bonder E.M. Feder H.H. Vasiliev J.M. Gelfand I.M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 4362-4367Crossref PubMed Scopus (70) Google Scholar). However, it is intercellular mechanical forces these on the data we a model of intercellular mechanotransduction contractile forces transmitted through intercellular adherens junctions mediate of channels in a that is to the of calcium-permeable channels observed in J. A. B. K. 1999; PubMed Scopus Google Scholar). calcium transients initiate actin assembly Physiol. 1998; PubMed Scopus Google Scholar), a that is at adjacent to intercellular because actin assembly induced by force M. Arora P. Ferrier J. McCulloch J Cell Sci. 1997; PubMed Google Scholar), actin adjacent to adherens junctions intercellular contacts and the to and the of channels to cells to of channels after intercellular In on the of data and the we suggest that connective tissue cells can coordinate responses to mechanical forces through adherens junctions. junctions mediate the of channels and the reorganization of actin We for cell for Langille and for Lee for flow and and for on the

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