Fibroblast Growth Factor-2 and Remodeled Type I Collagen Control Membrane Protrusion in Human Vascular Smooth Muscle Cells

Plasma membrane protrusion is fundamental to cell motility, but its regulation by the extracellular environment is not well elucidated. We have quantified lamellipodial protrusion dynamics in human vascular smooth muscle cells exposed to fibroblast growth factor 2 (FGF-2) and type I collagen, two distinct ligands presented to vascular cells during arterial remodeling. Video microscopy revealed that FGF-2 stimulated a modest increase in lamellipodial protrusion rate that peaked within 15 min. This response was associated with immediate but transient activation of Rac1 and was inhibited in cells infected with retrovirus containing cDNA encoding dominant-negative Rac1. A 1-h exposure to FGF-2 also set up a second phase of more striking lamellipodial protrusion evident at 24–36 h. This delayed response was most pronounced when cells were on type 1 collagen and was associated with FGF-2-induced expression of collagenase-1 that localized to the edge of protruding lamellipodia. Moreover, late membrane protrusion was inhibited when cells were on collagenase-resistant type I collagen, implicating degraded collagen as a mediator. For cells on collagen, the immediate activation of Rac1 by FGF-2 was followed by a sustained wave of Rac1 activation that was inhibited when cleavage of the collagen triple helix was prevented and also by blockade of αvβ3 integrin. We conclude that lamellipodial protrusion in smooth muscle cells can be regulated by waves of Rac1 activation, corresponding to the sequential presentation of FGF-2 and remodeled collagen. The findings thus reveal a previously unrecognized level of coordination among extracellular input that enables cells to maintain protrusive activity over prolonged periods. Plasma membrane protrusion is fundamental to cell motility, but its regulation by the extracellular environment is not well elucidated. We have quantified lamellipodial protrusion dynamics in human vascular smooth muscle cells exposed to fibroblast growth factor 2 (FGF-2) and type I collagen, two distinct ligands presented to vascular cells during arterial remodeling. Video microscopy revealed that FGF-2 stimulated a modest increase in lamellipodial protrusion rate that peaked within 15 min. This response was associated with immediate but transient activation of Rac1 and was inhibited in cells infected with retrovirus containing cDNA encoding dominant-negative Rac1. A 1-h exposure to FGF-2 also set up a second phase of more striking lamellipodial protrusion evident at 24–36 h. This delayed response was most pronounced when cells were on type 1 collagen and was associated with FGF-2-induced expression of collagenase-1 that localized to the edge of protruding lamellipodia. Moreover, late membrane protrusion was inhibited when cells were on collagenase-resistant type I collagen, implicating degraded collagen as a mediator. For cells on collagen, the immediate activation of Rac1 by FGF-2 was followed by a sustained wave of Rac1 activation that was inhibited when cleavage of the collagen triple helix was prevented and also by blockade of αvβ3 integrin. We conclude that lamellipodial protrusion in smooth muscle cells can be regulated by waves of Rac1 activation, corresponding to the sequential presentation of FGF-2 and remodeled collagen. The findings thus reveal a previously unrecognized level of coordination among extracellular input that enables cells to maintain protrusive activity over prolonged periods. In the mature vasculature, smooth muscle cells (SMCs) 1The abbreviations used are: SMC, smooth muscle cell; ECM, extracellular matrix; FGF, fibroblast growth factor; FBS, fetal bovine serum; EGFP, enhanced green fluorescent protein; GST, glutathione S-transferase; PBD, protein-binding domain. serve primarily as units of contraction. However, vascular SMCs also have the capacity to migrate and do so during vascular remodeling and disease. In these circumstances, SMCs migrate to regions in the vessel wall that have been damaged, for example by inflammation, where they replicate and elaborate the extracellular matrix (ECM). Although this process is designed to be reparative, it can also be deleterious leading to narrowing of the vessel lumen, restricted blood flow, and organ ischemia. SMC migration, like that of other cells, proceeds in a cycle that begins with the formation and protrusion of veil-like structures at the leading edge of the cell known as lamellipodia. Lamellipodia can stably attach to the ECM substrate, which enables traction forces to be generated to move the cell body forward. The trailing aspect of the cell then retracts to complete the cycle. Although all components of the migration cycle are necessary for cell translocation, protrusion of plasma membrane effectively leads the cell to its new location and is thus deemed to represent the essence of cell motility. Intensive investigation in recent years has elucidated the mechanistic basis of lamellipodial protrusion as well as the signaling paths that impinge on the protrusion machinery (1Pollard T.D. Nature. 2003; 422: 741-745Crossref PubMed Scopus (228) Google Scholar, 2Pollard T.D. Borisy G.G. Cell. 2003; 112: 453-465Abstract Full Text Full Text PDF PubMed Scopus (3341) Google Scholar). Central to the process is a dynamic network of branching actin filaments that serve to push membrane forward. Each new branch of actin in the lamellipodial network forms on the side of a parent filament, under the control of the Arp 2/3 complex of proteins. Assembly of the Arp 2/3 complex is activated by the Wiskott-Aldrich syndrome protein and related proteins. Rho family GTPases, in turn, activate the Wiskott-Aldrich syndrome proteins. Of the Rho GTPases, Rac1 is particularly important to lamellipodial protrusion because it can effectively switch the lamellipodial ruffling process on or off, depending on its state of activation (3Ridley A.J. Paterson H.F. Johnston C.L. Diekmann D. Hall A. Cell. 1992; 70: 401-410Abstract Full Text PDF PubMed Scopus (3106) Google Scholar, 4Hall A. Science. 1998; 279: 509-514Crossref PubMed Scopus (5270) Google Scholar, 5Nobes C.D. Hall A. J. Cell Biol. 1999; 144: 1235-1244Crossref PubMed Scopus (1224) Google Scholar). In contrast to growing data on the intracellular events underlying lamellipodial protrusion, less is known about the environmental signals that regulate these events. One extracellular factor that is known to generally influence SMC migration is fibroblast growth factor-2 (FGF-2, basic FGF) (6Jackson C.L. Reidy M.A. Am. J. Pathol. 1993; 143: 1024-1031PubMed Google Scholar, 7Pickering J.G. Uniyal S. Ford C. Chau T. Laurin M.A. Chow L.H. Ellis C.G. Fish J. Chan B.M.C. Circ. Res. 1997; 80: 627-637Crossref PubMed Scopus (71) Google Scholar). FGF-2 is liberated to act on SMCs following vascular injury and can stimulate SMCs to crawl from the medial vascular layer into the intimal layer (6Jackson C.L. Reidy M.A. Am. J. Pathol. 1993; 143: 1024-1031PubMed Google Scholar, 8Lindner V. Reidy M.A. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 3739-3743Crossref PubMed Scopus (600) Google Scholar). We have observed that SMC migration is particularly enhanced by FGF-2 when cells are on a substrate of type I collagen (7Pickering J.G. Uniyal S. Ford C. Chau T. Laurin M.A. Chow L.H. Ellis C.G. Fish J. Chan B.M.C. Circ. Res. 1997; 80: 627-637Crossref PubMed Scopus (71) Google Scholar). This apparent synergy between FGF-2 and type I collagen is noteworthy given the abundance of type I collagen fibrils in the interstitium of the vessel wall and the consequent need for migrating SMCs to navigate through this network. The basic mechanism by which FGF-2 promotes SMC migration is not fully defined, but current evidence suggests that FGF-2 alters the interplay between SMCs and the surrounding ECM (9Boilly B. Vercoutter-Edouart A.S. Hondermarck H. Nurcombe V. Le Bourhis X. Cytokine Growth Factor Rev. 2000; 11: 295-302Crossref PubMed Scopus (235) Google Scholar). In keeping with this concept, FGF-2 is one of a limited number of factors that can induce the expression of collagenase-1 in SMCs (10Pickering J.G. Ford C.M. Tang B. Chow L.H. Arterioscler. Thromb. Vasc. Biol. 1997; 17: 475-482Crossref PubMed Google Scholar), which could effectively clear a for SMC In that FGF-2-induced expression of collagenase-1 migrating SMCs to from the collagen substrate, which the to into the cell body S. Chow L.H. J.G. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). FGF-2-induced type I collagen to regulate the phase of the cycle. or not type I collagen, or a more in cell migration by lamellipodial protrusion is at the cell are distinct from events at the cell these two be for of the is the environmental can protrusion and also of plasma membrane this the of FGF-2 on plasma membrane protrusion in of lamellipodial activity in human vascular We evidence that lamellipodial protrusion is regulated by two and distinct of SMCs to FGF-2 in immediate but transient activation of Rac1 and transient protrusion of plasma This was followed by a prolonged phase of Rac1 activation and lamellipodial activity that was particularly striking when the cells were on a type 1 collagen This second wave of protrusion of plasma membrane was associated with collagenase-1 expression at the edge of protruding lamellipodia. Moreover, the second wave was on type I collagen cleavage and signaling through αvβ3 integrin. The findings a environmental are to a sequential activation for Rac1. Cell and of human vascular SMCs were by of of at the of J.G. J. J. 1993; PubMed Scopus Google Scholar). SMCs were in the second to and was and by for smooth muscle The cells were in with and and on of human collagen or collagen was from human plasma by as J.G. Chow L.H. S. Chan Am. J. Pathol. 2000; 453-465Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). and collagen type I were by in as B. C. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, S. C. Chan J.G. Am. J. Pathol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). collagenase-resistant collagen was from of of at the cleavage of the collagen H. X. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, X. H. J. S. J. Cell Biol. PubMed Scopus Google Scholar). the triple of type I collagen to cleavage by was from and control was from the cell of and of H. J.G. J. Biol. Full Text Full Text PDF PubMed Scopus Google was to human SMCs Rac1. cDNA encoding dominant-negative or Rac1 S. J. M.A. J. J. Biol. Full Text Full Text PDF PubMed Scopus Google cDNA were into the with to the The was and into were into the retrovirus cell by by D. Proc. Natl. Acad. Sci. U. S. A. 1993; PubMed Scopus Google by The was and was to human SMCs with for h. SMC was at on The cells stably or were with for 2 of was by and of was microscopy S. Chow L.H. J.G. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Chan B.M.C. J.G. J. 1998; PubMed Scopus Google Scholar). The cells with human collagen, or collagen were with contrast The were over a a and was at by the in a control cell and a of and was over a to maintain in the the cells were in with and membrane protrusion, or were and a was the of the two from the second the of membrane that during the The of all cell that over the or was as a of the cell from the of of the This was for the of over a when a The protrusion were and as a protrusion protrusion were in SMCs exposed to FGF-2 for the of to SMCs were by in with for h. the of a of FGF-2 was from the 1 or h. The cells were then 1 to SMCs were then with with the at which the lamellipodial protrusion rate was of collagenase-1 in human SMCs was in SMCs on and with The cells were with a human collagenase-1 and was and and and the activity of Rac1 and SMC was a of 1 as a protein with glutathione S. J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The the that a of Rac1 and the in its cDNA from the protein-binding of corresponding to was by from human cDNA and into the expression This was in and were by through a cell at and with The was with of and the was in of 1 1 SMCs on the substrate with the cells were in and with containing of protein was with of the at were by to a and human Rac1 or human was with and and The were by and the of Rac1 was with by cell that was not it to activity was in a to that for that SMCs were and was a protein by in as M.A. J. 1999; PubMed Scopus Google Scholar). was a human FGF-2 Plasma of human SMCs are cells that have one or more lamellipodial In the of a for SMC migration membrane activity is other ruffling and to membrane protrusion in microscopy and the cell the or were and and the of protruding regions were quantified by a The of the cell that protrusion was quantified in for the from which a protrusion rate was FGF-2 could influence plasma membrane membrane protrusion in human SMCs was under with following the of bovine and following the of in was a increase in plasma membrane protrusion following of data that within of of was a increase in the membrane protrusion rate This response a of growth factor and and The substrate on which SMCs were on this immediate protrusion response to with observed between SMCs on type I collagen, or not the in the SMCs can be to crawl for sustained periods. plasma membrane dynamics the of FGF-2 to the in the at this was a increase in lamellipodial activity that was more pronounced that following FGF-2 In observed that the of the late protrusion response on the ECM plasma membrane protrusion rate for SMCs on collagen was that for SMCs on The protrusive response for SMCs on type I collagen not to be a of because SMCs collagen and (7Pickering J.G. Uniyal S. Ford C. Chau T. Laurin M.A. Chow L.H. Ellis C.G. Fish J. Chan B.M.C. Circ. Res. 1997; 80: 627-637Crossref PubMed Scopus (71) Google and the of not a response to FGF-2 that was as as that for SMCs on type I collagen or not In FGF-2 immediate lamellipodial protrusion of SMCs but also SMCs with a pronounced to and for a sustained The of the sustained response on the ECM with apparent interplay between FGF-2 and type I collagen. FGF-2 at the Cell and type I collagen could membrane protrusion of SMCs the that FGF-2 is known to induce the expression of collagenase-1 (10Pickering J.G. Ford C.M. Tang B. Chow L.H. Arterioscler. Thromb. Vasc. Biol. 1997; 17: 475-482Crossref PubMed Google Scholar). This the that lamellipodial activity be by of the collagen that collagenase-1 was in SMCs and to the SMCs were a was evident in SMCs on type I collagen or However, with collagenase-1 was observed at the cell the of the as signals at the edge of the the of on lamellipodial membrane protrusion of SMCs on collagenase-resistant collagen. This substrate was from the of a in the corresponding to the collagenase-1 cleavage This the collagen triple helix to cleavage at the cleavage of the the of the triple helix H. X. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, X. H. J. S. J. Cell Biol. PubMed Scopus Google Scholar). in the and of the of FGF-2 to stimulate sustained membrane protrusion was when SMCs were on collagenase-resistant collagen. The lamellipodial protrusion rate of SMCs migrating on collagen was that of SMCs on collagen and to the protrusion for SMCs on the capacity to a type I collagen substrate lamellipodial activity in in SMCs the membrane protrusive of FGF-2 in SMCs generated human SMCs dominant-negative Rac1 or Rac1 SMCs and expression was by SMCs with retrovirus containing cDNA encoding or with cDNA in a the response to FGF-2 in control and human SMCs dominant-negative Rac1 increase in lamellipodial protrusion during the the of In SMCs Rac1 that could over of the membrane cells membrane protrusion rate under and was increase in lamellipodial protrusion the of protrusion was also in and that were with in SMCs infected with retrovirus containing cDNA for a late response to FGF-2 that was to that for FGF-2 membrane protrusion rate for cells on and for SMCs on type I collagen and with a response for SMCs on collagenase-resistant collagen. In SMCs dominant-negative Rac1 increase in plasma membrane protrusion prolonged with protrusion of SMCs Rac1 that of SMCs on collagen with and the lamellipodial protrusion rate was not by exposure to In the membrane protrusion rate in when these cells were on collagenase-resistant collagen. of signaling the by a collagen substrate that be FGF-2 Rac1 in a and FGF-2 Rac1 and to the of activation, Rho activity were on SMCs on collagen, or collagenase-resistant collagen, and FGF-2 in the level of Rac1 was by but the of activation on the ECM For SMCs on Rac1 activation was FGF-2 The activation was and the of Rac1 to FGF-2 and for the h. For SMCs on collagen, also was immediate and transient activation of this was followed by a second wave of Rac1 activation that up to Rac1 activity for SMCs on collagen was that for SMCs on SMCs not stimulated with FGF-2 evidence for Rac1 activation at or late of the ECM was in SMCs on or collagen under However, the level of activity not following FGF-2 The abundance of was also not by FGF-2 FGF-2 to activate Rac1. Moreover, the of Rac1 activation is by the ECM substrate that a prolonged wave of Rac1 activation when SMCs are on type I collagen. this second wave of Rac1 activation was on of the collagen substrate, SMCs were when on collagenase-resistant collagen. activation of Rac1 in response to FGF-2 was observed under these the second phase was data from revealed that Rac1 activity at was to that of cells on collagen the delayed phase of Rac1 activation at that the underlying collagen substrate be remodeled by cleavage of the triple implicating remodeled collagen as a of Rac1 Rac1 and in SMCs by αvβ3 to the through which remodeled collagen the delayed phase of membrane protrusion in and of type I collagen is known to for αvβ3 that do not in type I collagen Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), a process to new signals to cells within a collagen J. 1999; PubMed Scopus Google Scholar). Moreover, the has been in Rac1 activation in A. J. Cell Biol. 2003; PubMed Scopus Google Scholar). membrane protrusion of SMCs on collagen was by αvβ3 SMCs were stimulated with FGF-2 in the of αvβ3 or control in blockade of αvβ3 on the immediate protrusive response to the delayed by membrane protrusion at was inhibited In and with this Rac1 activation at was inhibited when SMCs were with the FGF-2 to during the of Rac1 and of two distinct waves of Rac1 activation for cells on type I collagen, and the of collagen remodeling in the second the as to FGF-2 to be for of Rac1 FGF-2 in SMCs on type I collagen were stimulated with FGF-2 for of to which the was and cells were to The cells were then in with the at which SMCs were for membrane protrusion and Rac1 in lamellipodial protrusion at were observed with as as 1 of with to A was observed for Rac1 activation The late activation of Rac1 for SMCs on collagen was observed with as as of exposure to FGF-2 was a for the second wave of Rac1 activation and lamellipodial protrusion, the cell not by FGF-2 at the the second phase was in SMCs by has been that collagenase-1 expression in can be by activation of Rac1 Science. 1998; PubMed Scopus Google Scholar). This the that the immediate activation of Rac1 by FGF-2 a in the phase of Rac1 activation and membrane collagenase-1 expression in SMCs was by SMCs were infected with retrovirus containing cDNA encoding or dominant-negative and collagenase-1 protein was by in SMCs Rac1 modest expression of collagenase-1 in the of with SMCs or dominant-negative Rac1 collagenase-1 of SMCs with FGF-2 collagenase-1 and this response was not in SMCs The level of collagenase-1 generated when were stimulated with FGF-2 was that of and also that of control SMCs stimulated with findings that collagenase-1 expression is not by Rac1. the of Rac1 activity be a of the leading to the second wave of Rac1 However, Rac1 activation not to be the mechanism by which FGF-2 collagenase-1 expression in and are also In this have that lamellipodial protrusion of human vascular SMCs is regulated by the of FGF-2 and type I collagen, two distinct ligands that are presented to SMCs under of vascular remodeling. environmental the protrusion of plasma membrane a dynamic mechanism that and of SMCs to FGF-2 leads to immediate activation of Rac1 and protrusion of lamellipodia. This response to FGF-2 is followed by the of collagenase-1 of collagenase-1 to lamellipodial and of the type I collagen The remodeled collagen, in turn, a second phase of Rac1 activation, αvβ3 that is sustained and associated with more pronounced protrusion of the plasma membrane The current the that Rac1 can be activated within of cells to FGF-2 not stimulate activation of or in a in activation by FGF-2 and the of interplay among of and activation, in contrast to that observed in activated cells C.D. Hall A. Cell. Full Text PDF PubMed Scopus Google Scholar). The of activation of Rac1 in SMCs by FGF-2 was a of the lamellipodial by the immediate in plasma membrane protrusion that could be by dominant-negative Rac1. the protrusive response was and it 15 min. that Rac1 activation by FGF-2 in of a However, in to immediate membrane protrusion, this exposure to FGF-2 a of collagenase-1 expression and collagen that the more sustained wave of Rac1 The of of has for growth growth factor is at and late for cells to the cell cycle A. Cell Biol. PubMed Scopus Google Scholar). is to that a for the regulation of cell motility. the the two of activation for lamellipodial protrusion were by (FGF-2) and environmental This is as to a growth factor at FGF-2 not need to be during the second wave of Rac1 activation for this wave to a 1-h exposure of SMCs on type I collagen to FGF-2 was to the cells to plasma membrane up to of collagenase-1 expression by FGF-2 was for the delayed phase of Rac1 activation and membrane expression by FGF-2 was by Rac1. This suggests that the activation of Rac1 by FGF-2 was to the second wave of Rac1 the collagenase-1 expression not to be on Rac1 activation, and other are Moreover, the two of Rac1 activation are the factors that stimulated of the two We previously that a of the collagenase-1 in response to FGF-2 was to the plasma membrane S. Chow L.H. J.G. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of collagenase-1 to the cell has also been observed in J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). In the current that in collagenase-1 was localized to the leading edge of lamellipodial This is in keeping and that degraded type I collagen could be the leading of SMCs S. Chow L.H. J.G. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), and it the that membrane protrusion be by collagen Moreover, the current that of was when SMCs were on collagenase-resistant collagen degraded collagen as a for the delayed phase of lamellipodial be at two by which collagen could membrane protrusion at the leading edge of the by collagen, a is generated that effectively for membrane to be for that has been to the triple helix cleavage and the collagen have a capacity for type I collagen A.J. V. J. J. Cell Sci. 1998; PubMed Google Scholar). type I collagen also which serve as ligands for on the cell Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, Res. 1992; PubMed Scopus Google Scholar). the of between collagen and αvβ3 is less that of collagen to the and of lamellipodial membrane be over to the collagen have also been to stimulate cleavage of with associated in SMC B. J. Cell Biol. 1999; PubMed Scopus Google Scholar). remodeling of the complex thus be by which type I collagen cleavage the from its However, in to plasma membrane for protrusion, the current findings that degraded collagen also the machinery for plasma membrane protrusion by Rac1. a collagenase-resistant collagen substrate, Rac1 activation was However, Rac1 was activated when collagen remodeling and this activation was by αvβ3 integrin. that other in also in the second wave of Rac1 A has been to be for growth Rac1 activation in A. J. Cell Biol. 2003; PubMed Scopus Google Scholar). a from collagen to degraded collagen to serve as a necessary switch that a second for of this be and previously events from activation, as and be J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. Cell Biol. 1998; PubMed Scopus Google Scholar, A.J. M.A. Borisy Science. 2003; PubMed Scopus Google Scholar). For cell translocation, membrane protrusion at the cell be with membrane at the We previously that FGF-2-induced collagenase-1 activity the cell to its trailing aspect from a type I collagen In the of collagen the cell could effectively the cell from translocation, FGF-2-induced collagen for smooth of the cell and thus of the cell (10Pickering J.G. Ford C.M. Tang B. Chow L.H. Arterioscler. Thromb. Vasc. Biol. 1997; 17: 475-482Crossref PubMed Google Scholar, S. Chow L.H. J.G. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In of the current it is apparent that collagen as environmental control for protrusion and the and of these two events. have that FGF-2 activity and thus not stimulate the migration of SMCs (7Pickering J.G. Uniyal S. Ford C. Chau T. Laurin M.A. Chow L.H. Ellis C.G. Fish J. Chan B.M.C. Circ. Res. 1997; 80: 627-637Crossref PubMed Scopus (71) Google Scholar, C. D. B. J. PubMed Scopus Google Scholar). is that FGF-2 has a in the or of migrating However, a and have been for example by a of the by FGF-2 and collagen to have a over protrusion and This of mechanism for between the and of a migrating injury to the SMCs are liberated from membrane they migrate through the to the Circ. Res. PubMed Scopus Google Scholar). In of the current this of SMCs the medial is at in by the exposure of SMCs to FGF-2 and to type I collagen. in the exposed to with a ECM that is in collagen but in ECM SMC migration proceeds during this phase of vascular but it is less striking in the following vascular on the current that in the of FGF-2 the from a type I collagen environment to a ECM environment a for SMC migration, by of activation of Rac1 and less membrane In lamellipodial protrusion in human SMCs can be regulated by waves of Rac1 activation, corresponding to the sequential presentation of FGF-2 and remodeled collagen. FGF-2 immediate and transient Rac1 activation but also of type I collagen, a that sustained activation of Rac1 αvβ3 integrin. This activation for Rac1 suggests a previously unrecognized level of coordination among extracellular input that enables SMCs to maintain lamellipodial protrusive activity over prolonged periods. of collagen also promotes the of the of the cell from its substrate, the findings also a for protrusion and We for the cell

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