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Article |
Correspondence to Stephen J. Weiss: sjweiss{at}umich.edu
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Abstract |
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Introduction |
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Like all members of the MMP family, MMP-2 and MMP-9 are synthesized as latent enzymes (Egeblad and Werb, 2002, Seiki, 2002). However, coincident with the expression of tissue-invasive or morphogenic processes, secreted MMP-2 and MMP-9 are activated. With specific regard to angiogenesis, the serine proteinase plasmin has been proposed to act as an activator of both MMP-2 and MMP-9, whereas multiple members of the membrane-anchored family of MMPs (i.e., membrane-type [MT]1-, 2-, 3-, 4-, 5-, and 6-MMP) can process the MMP-2 zymogen to its active form (Pepper, 2001; Davis et al., 2002; Seiki, 2002). Surface localization of the activated metalloproteinases may be critical for allowing cells to migrate within dense connective tissues, as binding interactions between MMP-2 and the vß3 integrin, and between MMP-9 and the cell surface proteoglycan CD44, have been associated with invasive/angiogenic phenotypes (Brooks et al., 1996, 1998; Yu and Stamenkovic, 1999; Silletti et al., 2001).
Despite the wealth of evidence supporting a role for MMP-2, MMP-9, plasminogen, or MT1-MMP activity in angiogenic events in vivo (Brooks et al., 1998; Itoh et al., 1998; Bergers et al., 2000; Zhou et al., 2000; Heissig et al., 2003), the means by which these proteinases exert their effects remain largely undefined. Long thought to confine their activity to degrading ECM components, increasing evidence suggests that MMPs may modulate endothelial cell function indirectly by activating latent cytokines, cleaving membrane-anchored targets, releasing matrix-bound growth factors, or generating bioactive neopeptides (Egeblad and Werb, 2002; Heissig et al., 2003). Consequently, it remains unclear whether MMP-2, MMP-9, their cognate receptors, or the upstream proteinases responsible for their activation, directly support the crucial collagen-remodeling events necessary to drive the morphogenic programs associated with angiogenesis.
To identify the proteolytic systems required for neovessel formation within a physiologically relevant interstitial matrix, three-dimensional (3-D) gels of cross-linked type I collagen were seeded with tissue explants or endothelial cells isolated from mice harboring inactivating mutations in either the plasminogen, MMP-2, MMP-9, ß3 integrin, CD44, or MT1-MMP genes. Unexpectedly, we demonstrate that neovessel formation proceeds in unperturbed fashion in the absence of either plasminogen, MMP-2, MMP-9, the ß3 integrin, or CD44. Instead, the membrane-anchored collagenase MT1-MMP plays a required role in conferring endothelial cells with the ability to both proteolytically remodel type I collagen and express a collagen-invasive phenotype critical to the tubulogenic process.
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Results |
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Capillary morphogenesis proceeds independently of the MMP-2vß3 or MMP-9CD44 axes
The association of catalytically active MMP-2 with the vß3 integrin has been reported to regulate the angiogenic response (Brooks et al., 1996, 1998; Silletti et al., 2001), but the role that this complex plays in directing invasive/tubulogenic programs has not been defined. To determine the relative roles of MMP-2 and
vß3 in neovessel formation, we monitored vessel outgrowth and morphology in explants isolated from MMP-2null or
vß3-null mice. Although wild-type explants expressed both MMP-2 and ß3, as assessed by RT-PCR (not depicted), MMP-2null and wild-type littermate explants mounted an indistinguishable tubulogenic response, without significant differences in mean capillary length or density (Figs. 2 A and 3 C). Furthermore, morphogenesis proceeded in normal fashion, with a ring of endothelial cells circumscribing a patent lumen (Fig. 2 A). Consistent with an MMP-2independent tubulogenic program, neither vessel outgrowth nor vessel morphology was inhibited in the absence of the ß3 integrin (Figs. 2 B and 3 C).
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In contrast with wild-type explants, tissues isolated from MT1-MMP/ mice are completely unable to generate neovessels during a 7-d culture period (Fig. 5 A). Co-cultures of MT1-MMPnull explants with wild-type aorta rings demonstrate that soluble inhibitors of capillary formation are not released from the knockout tissues and that wild-type tissues do not generate soluble factors that are able to rescue the null phenotype (Fig. 5 A). Similar, if not identical, results are obtained when explants of lung, myocardium, or skin are recovered from MT1-MMPnull mice and tested ex vivo (unpublished data). Furthermore, although neovessel formation by control aortic explants resulted in the release of 6.2 ± 1.1 µg hydroxyproline, MT1-MMP/ explants released only 1.2 ± 0.6 µg hydroxyproline in the course of a 7-d culture period. In the presence of TIMP-2, collagenolysis by wild-type and MT1-MMP/ explants was inhibited completely (0.4 ± 0.3 µg and 0 ± 0 µg hydroxyproline released, respectively; n = 3). Though MT1-MMP has been posited to regulate cell function by activating latent TGFß or generating denatured collagen products that mediate integrin signaling (Heissig et al., 2003), neither the addition of active TGFß nor that of proteolyzed collagen affected the MT1-MMP/ phenotype (unpublished data).
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Finally, we sought to determine whether the ability of MT1-MMP or MT2-MMP to confer invasive activity to MT1-MMP/ endothelial cells could be extended from homogenous 3-D constructs of type I collagen in the in vitro setting to a more complex interstitial barrier in vivo. Hence, wild-type or MT1-MMPnull endothelial cells transduced with control, MT1-MMP, MT2-MMP, or MT3-MMP retroviral expression vectors were labeled with either fluorescent microbeads or GFP and cultured atop the type I/III collagenrich chick chorioallantoic membrane (CAM; Fig. 7 C). Consistent with the results obtained in vitro, wild-type, but not MT1-MMPnull endothelial cells, were able to penetrate deeply into the CAM interstitium. Furthermore, although GFP-labeled wild-type endothelial cells adopted an elongated phenotype and displayed morphogenic properties by generating tubular structures in the in vivo setting, MT1-MMPnull endothelial cells remained spherical in shape and did not form tubules (Fig. 7 C). Though the MT1-MMP/ phenotype was not rescued by overexpressing MT3-MMP, tissue-invasive activity was restored fully by expressing either MT1-MMP or MT2-MMP (Fig. 7 C). Thus, membrane-anchored collagenases uniquely confer expressing cells with the proteolytic machinery necessary to drive the invasive phenotype critical to morphogenic programs in collagen-rich environments in vitro and in vivo.
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Discussion |
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Accumulating evidence supports an angiogenic scheme in which endothelial cellassociated MMP-2 and MMP-9 drive endothelial migration, invasion, or tubulogenesis (Haas et al., 1998; Koivunen et al., 1999; Lyden et al., 1999; Xu et al., 2001). Because MT1-MMP proteolyzes the MMP-2 zymogen to its active form which, in turn, can activate MMP-9 (Seiki, 2002; Toth et al., 2003), we speculated initially that all three MMPs would form a collaborative network to drive the angiogenic response. Likewise, reports documenting the ability of vß3 and CD44 to localize MMP-2 and MMP-9, respectively, to the migrating front of tissue-invasive cells are consistent with a proteolytic model in which integrins and transmembrane glycoproteins act as docking sites for the assembled proteinases (Brooks et al., 1996; Yu and Stamenkovic, 1999; Rolli et al., 2003). Nonetheless, despite the appeal of such schemes, neither MMP-2,
vß3, MMP-9, nor CD44 played a required role in neovessel formation, endothelial cell collagen invasion, or collagenolytic activity ex vivo. Likewise, although plasmin has been linked to the angiogenic process (Carmeliet and Jain, 2000; Pepper, 2001), plasminogen-null explants displayed no defects in our ex vivo model. In contrast, tissue explants recovered from MT1-MMP/ mice were completely unable to mount a tubulogenic response when suspended in collagen gels. Furthermore, consistent with the proposition that collagenolytic activity is required to support endothelial cell invasion within a type I collagenrich environment (Fisher et al., 1994; Haas et al., 1998; Seandel et al., 2001; Davis et al., 2002), MT1-MMPnull endothelial cells were unable to degrade subjacent collagen in a serum-containing milieu. Apparently, MT1-MMP is the major, if not sole, collagenolysin operative in mouse endothelial cells that is capable of mediating the pericellular dissolution of type I collagen under physiologic conditions. Given that the MT1-MMP zymogen undergoes efficient processing to its active form via a proprotein convertasedependent process (Yana and Weiss, 2000), plasmin-mediated processing of MT1-MMP does not play a required role in this system. Although mouse endothelial cells express soluble collagenases (e.g., MMP-13, MMP-2, and MMP-8) and can use plasmin to activate these proteinases, these MMPs were unable to mount a focal collagenolytic effect in the presence of serum antiproteinases (unpublished data). Hence, in the absence of MT1-MMP activity, mouse endothelial cells fail to degrade collagen or negotiate collagenous barriers. As human endothelial cell tubulogenesis is also sensitive to TIMP-2, but not TIMP-1 (Lafleur et al., 2002; Collen et al., 2003), we posit that MT1-MMP and/or MT2-MMP play(s) a dominant role in directing angiogenesis in humans as well.
Despite the correlation between collagenolytic and invasive activity, MT1-MMP hydrolyzes not only type I collagen, but also a variety of noncollagenous targets (Seiki, 2002; Egeblad and Werb, 2002). Consequently, we cannot eliminate the possibility that MT1-MMP cleaves type I collagen in tandem with other substrates in a fashion necessary to affect an invasive and/or tubulogenic program. Our data do, however, rule out recently proposed models wherein MT1-MMP drives invasion by either processing the vß3 integrin or cleaving CD44 (Deryugina et al., 2000; Kajita et al., 2001; Mori et al., 2002). Furthermore, a more generalized defect in cell adhesion, migration, or invasion that might be consistent with MT1-MMPdependent proteolysis of integrins, cadherins, growth factors, or surface enzymes is not supported by our observations that MT1-MMP/ cells migrate at normal rates across collagen-coated surfaces and invade cross-linked fibrin barriers. Though recent studies have suggested that MT1-MMP can regulate endothelial cell migration (Gálvez et al., 2002), these conclusions are founded on the use of neutralizing antibodies directed against MT1-MMP. Because these antibodies do not recapitulate the MT1-MMP/ phenotype and, in independent studies, affected the activity of multiple membrane-anchored as well as secreted MMPs (unpublished data), caution should be exercised in assuming their specificity or utility as MT1-MMP inhibitors.
The striking defects in collagenolytic and invasive activity, as well as in neovessel formation, displayed by MT1-MMP/ tissues seem at odds with the fact that the null animals develop normally (Holmbeck et al., 1999; Zhou et al., 2000). In this regard, it is interesting to note that during embryogenesis, as well as perinatally, the type I collagen content of most tissues is low relative to the content in the postnatal state (Van Exan and Hardy, 1984; Carver et al., 1993). As a possible consequence, newborn null animals appear normal and only begin to display serious skeletal and connective tissue abnormalities after the first week of birth (Holmbeck et al., 1999; Zhou et al., 2000). Hence, although the ECM composition of the developing animal may afford MT1-MMP/ animals a protected status, we posit that the increased deposition of type I collagen that arises as a consequence of the mechanical demands of adult life initiates the onset of the pathologic states observed in the knockout mice. Indeed, though null animals display an apparently normal vasculature at birth, Zhou et al. (2000) have reported that angiogenic responses in 15-d-old MT1-MMP/ animals are abrogated in collagen-rich corneal tissues. Nonetheless, even in collagen-replete tissues, our results suggest that angiogenesis in fibrin-rich fields (e.g., wounds) may proceed normally in MT1-MMPnull mice because MT3-MMP, though largely devoid of collagenolytic activity, can function as an efficient fibrinolysin (Hotary et al., 2002).
Together, our observations appear to be at variance with other in vitro or in vivo studies concluding that plasminogen, MMP-2, or MMP-9 plays a required role in the angiogenic process (Carmeliet and Jain, 2000; Brodsky et al., 2001; Pepper, 2001). However, it should be noted that defects in angiogenesis have not been observed uniformly in either plasminogen/, MMP-2/, or MMP-9/ mice in response to wounding (Romer et al., 1996; Itoh et al., 1998) or tumor growth (Bergers et al., 2000; Hamano et al., 2003). Furthermore, vß3/ mice mount an exaggerated angiogenic response in a range of pathophysiologic settings (Reynolds et al., 2002). In cases where MMP-2 deficiency has been shown to affect neovascularization, a partial reduction in the angiogenic response (
30%) has been most frequently described (Itoh et al., 1998; Berglin et al., 2003; Guedez et al., 2003). In contrast, MMP-9deficient mice can, in some cases, display more significant defects in angiogenesis in vivo, but this effect has been ascribed largely to the ability of the metalloproteinase to release matrix-bound forms of VEGF (Bergers et al., 2000). Indeed, vascular defects in these animals are reversed by the exogenous application of VEGF, despite the continued absence of MMP-9 (Engsig et al., 2000; Heissig et al., 2003). Nonetheless, under defined circumstances, plasminogen, MMP-2, MMP-9,
vß3, or CD44 can play an important role in modifying angiogenic events in vivo (Carmeliet and Jain, 2000; Pepper, 2001; Davis et al., 2002; Heissig et al., 2003; Oh et al., 2004), but based on our results, these effects are more likely exerted in a fashion independent of the matrix remodeling events associated strictly with invasion or tubulogenesis within the 3-D interstitium. As the ex vivo models used herein largely obviate a required role for endogenous growth factors, chemokines, or immune cell populations, it may well develop that these latter players serve as preferred targets for plasminogen, MMP-2, or MMP-9 in vivo. Similarly, the ex vivo model may circumvent a requirement for basement membrane proteolysis, a key step in the initiation of the angiogenic process, though it should be noted that angiogenesis can proceed in a normal fashion in vivo even in the combined absence of MMP-2 and MMP-9 (Baluk et al., 2004). Clearly, a mounting number of observations describing normal, or near normal, tubulogenic programs in MMP-2 or MMP-9null animals (Andrews et al., 2000; Bergers et al., 2000; Wiseman et al., 2003) strongly suggest that tubulogenic programsincluding angiogenesiscan proceed in the absence of these downstream MMPs. As such, the rules we have established for generating patent neovessels in collagen-rich tissues raise the possibility that MT1-MMP and perhaps MT2-MMP play dominant roles in driving a variety of tubulogenic programs in the in vivo, postnatal setting.
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Materials and methods |
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After 7 d in culture, the collagen gelembedded fragments were fixed, the endothelial cells were immunostained with antimouse CD31 antibody (BD Biosciences) followed with Alexa Fluor 488 antirat IgG secondary antibody (Molecular Probes), and the nuclei were visualized with DAPI (Vector Laboratories). Samples were mounted in Vector Shield (Vector Laboratories) and fluorescent or light images were captured by a microscope (DMLB; Leica; 5x/0.7 NA or 10x/0.7 NA objective lens) equipped with a SPOT RT camera (Diagnostic Instruments). Neovessel length was determined with SPOT software (Diagnostic Instruments) after calibration, using an objective micrometer. For light and transmission electron microscopic studies, gels were fixed with 2% glutaraldehyde and 1.5% PFA in 0.1 M sodium cacodylate, pH 7.4 (Hotary et al., 2002). Neovessel density was quantified by counting the number of tubules in six or more cross sections taken 5 mm from the edge of the cultured aortic rings in all four quadrants surrounding the embedded explants, after capturing the images with a microscope (DMLB; Leica; 20x/0.7 NA objective lens) fitted with a SPOT RT camera. To visualize sites of collagen matrix remodeling, we stained frozen sections with either the polyclonal antibody against cleaved type I collagen (gift of A.R. Poole, McGill University, Montreal, Canada) or a monoclonal antibody directed against denatured type I collagen (Xu et al., 2001). Type IV collagen and laminin were identified with polyclonal antitype IV collagen (Oncogene Research Products) and monoclonal antilaminin (Sigma-Aldrich) antibodies. Chicken types I and III collagen were localized using antichicken types I and III collagen antibodies, respectively (CHEMICON International). Alexa Fluor 488 or 594conjugated antimouse or antirabbit antibodies (Molecular Probes) were used as secondary antibodies. Sirius red staining was performed as described by Canham et al. (1999). Type I collagen degradation during neovessel formation was quantified by hydroxyproline assay (Creemers et al., 1997).
Endothelial cell invasive activity
Mouse dermal endothelial cells were isolated as described by Murphy et al. (1998). The isolated cells were cultured on gelatin-coated dishes in RPMI 1640 media with 5% mouse serum and supplemented with 100 µg/ml endothelial cell growth supplement (BD Biosciences). The endothelial characteristics of the isolated cells were confirmed by von Willebrand factor, CD31, and VE-cadherin staining (Murphy et al., 1998). DiI-Ac-LDL uptake was >99%. To assess invasive activity, confluent monolayers of microvascular endothelial cells were cultured atop type I collagen gels (2.2 mg/ml), fibrin gels (3.0 mg/ml), or acellular explants of human dermis (Alloderm; Life Cell) in the upper compartment of Transwell dishes (Costar) and exposed to a chemotactic gradient of VEGF (100 ng/ml) and HGF (50 ng/ml).
Collagen film degradation assay
Type I collagen gel films (100 µg) prepared on glass coverslips were labeled with tetramethylrhodamine isocyanate (Molecular Probes) for 45 min. Microvascular endothelial cells were cultured atop the collagen gels in the presence of 100 ng/ml VEGF, 50 ng/ml HGF, and 5% autologous serum. After 7 d, the samples were fixed, polymerized actin was visualized with Alexa Fluor 488 phalloidin (Molecular Probes), and fluorescent images were obtained by a laser scanning fluorescent microscope (model LSM 510; Carl Zeiss MicroImaging, Inc.) equipped with acquisition software (Version 3.2; Service Pck 2) using either 40x or 63x C-Apochromat (1.2 NA) water immersion objective lenses at 25°C. Samples were mounted in Vector Shield (Vector Laboratories).
Chick CAM assays
Endothelial cell invasion, before or after retroviral transduction, was determined in vivo using 11-d-old chick embryos wherein wild-type or MT1-MMPnull endothelial cells were seeded atop the CAM for 3 d (Cameron et al., 2000). To visualize endothelial cells, 105 cells were either labeled with 0.05 µm fluoresbrite carboxylate microspheres (Polysciences) or transduced with a GFP retroviral vector. The mean depth of endothelial invasion was determined by measuring the distance from the CAM surface to the leading front of two or more invading endothelial cells in 10 or more randomly selected fields, as assessed with a microscope (DMLB; Leica)/SPOT RT camera system in at least two experiments.
Retroviral gene transfer
HA-tagged human MT1-MMP cDNA; soluble MT1-MMP (Met1-Gly535 that lacks the COOH-terminal transmembrane and cytosolic domains of the wild-type proteinase, and MT1-MMPsol), a catalytically inactive full-length form of MT1-MMP that harbors an E240 to A substitution in its catalytic domain (MT1-MMPE/A); or mouse cDNA clones for MT2-MMP and MT3-MMP (provided by M. Seiki, University of Tokyo, Tokyo, Japan) were subcloned into pRET2 retroviral vector derived from the Moloney murine leukemia virusbased MFG backbone (Morita et al., 2001). The control pRET vector carried an EGFP cDNA. Subconfluent monolayers of the isolated endothelial cells were cultured in the retroviral supernatant for 12 h in the presence of 100 µg/ml endothelial cell growth supplement and collagen invasion and degradation assays were performed 24 h later. The expression of MT1-MMP, MT2-MMP, and MT3-MMP was confirmed by Western blot analysis using polyclonal antiMT1-MMP antibody (Yana and Weiss, 2000) and monoclonal antimouse MT2-MMP and MT3-MMP antibodies (Calbiochem), respectively.
RT-PCR analysis
Endothelial cells were cultured atop type I collagen gels in the presence of 100 ng/ml VEGF and 50 ng/ml HGF in 10% serum, and total RNA was isolated using TRIzol reagent (GIBCO BRL). RT-PCR was performed using One-Step RT-PCR System reagent (Life Technologies). The identities of the PCR products were confirmed by sequence analysis.
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Acknowledgments |
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This work was supported by National Institutes of Health grants R01 CA071699 and R01 CA088308.
Submitted: 3 May 2004
Accepted: 28 September 2004
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References |
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Andrews, K.L., T. Betsuyaku, S. Rogers, J.M. Shipley, R.M. Senior, and J.H. Miner. 2000. Gelatinase B (MMP-9) is not essential in the normal kidney and does not influence progression of renal disease in a mouse model of Alport Syndrome. Am. J. Pathol. 157:303311.
Atkinson, S.J., M.L. Patterson, M.J. Butler, and G. Murphy. 2001. Membrane type 1 matrix metalloproteinase and gelatinase A synergistically degrade type 1 collagen in a cell model. FEBS Lett. 491:222226.[CrossRef][Medline]
Baluk, P., W.W. Raymond, E. Ator, L.M. Coussens, D.M. McDonald, and G.H. Caughey. 2004. Matrix metalloproteinase-2 and -9 expression increases in Mycoplasma-infected airways but is not required for microvascular remodeling. Am. J. Physiol. Lung Cell. Mol. Physiol. 287:L307L317.
Bergers, G., R. Brekken, G. McMahon, T.H. Vu, T. Itoh, K. Tamaki, K. Tanzawa, P. Thorpe, S. Itohara, Z. Werb, and D. Hanahan. 2000. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol. 2:737744.[CrossRef][Medline]
Berglin, L., S. Sarman, I. van der Ploeg, B. Steen, Y. Ming, S. Itohara, S. Seregard, and A. Kvanta. 2003. Reduced choroidal neovascular membrane formation in matrix metalloproteinase-2-deficient mice. Invest. Ophthalmol. Vis. Sci. 44:403408.
Brodsky, S., J. Chen, A. Lee, K. Akassoglou, J. Norman, and M.S. Goligorsky. 2001. Plasmin-dependent and -independent effects of plasminogen activators and inhibitor-1 on ex vivo angiogenesis. Am. J. Physiol. Heart Circ. Physiol. 281:H1784H1792.
Brooks, P.C., S. Stromblad, L.C. Sanders, T.L. von Schlascha, R.T. Aimes, W.G. Stetler-Stevenson, J.P. Quigley, and D.A. Cheresh. 1996. Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin vß3. Cell. 85:683693.[Medline]
Brooks, P.C., S. Silletti, T.L. von Schlascha, M. Friedlander, and D.A. Cheresh. 1998. Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity. Cell. 92:391400.[Medline]
Cameron, M.D., E.E. Schmidt, N. Kerkvliet, K.V. Nadkarni, V.L. Morris, A.C. Groom, A.F. Chambers, and I.C. MacDonald. 2000. Temporal progression of metastasis in lung: cell survival, dormancy, and location dependence of metastatic inefficiency. Cancer Res. 60:25412546.
Canham, P.B., H.M. Finlay, J.A. Kiernan, and G.G. Ferguson. 1999. Layered structure of saccular aneurysms assessed by collagen birefringence. Neurol. Res. 21:618626.[Medline]
Carmeliet, P., and R.K. Jain. 2000. Angiogenesis in cancer and other diseases. Nature. 407:249257.[CrossRef][Medline]
Carver, W., L. Terracio, and T.K. Borg. 1993. Expression and accumulation of interstitial collagen in the neonatal rat heart. Anat. Rec. 236:511520.[Medline]
Collen, A., R. Hanemaaijer, F. Lupu, P.A. Quax, N. van Lent, J. Grimbergene, E. Peters, P. Koolwijk, and V.W. van Hinsbergh. 2003. Membrane-type matrix metalloproteinase-mediated angiogenesis in a fibrin-collagen matrix. Blood. 101:18101817.
Creemers, L.B., D.C. Jansen, A. van Veen-Reurings, T. van den Bos, and V. Everts. 1997. Microassay for the assessment of low levels of hydroxyproline. Biotechniques. 22:656658.[Medline]
Davis, G.E., K.A. Pintar Allen, R. Salazar, and S.A. Maxwell. 2001. Matrix metalloproteinase-1 and -9 activation by plasmin regulates a novel endothelial cell-mediated mechanism of collagen gel contraction and capillary tube regression in three-dimensional collagen matrices. J. Cell Sci. 114:917930.
Davis, G.E., K.J. Bayless, and A. Mavila. 2002. Molecular basis of endothelial cell morphogenesis in three-dimensional extracellular matrices. Anat. Rec. 268:252275.[CrossRef][Medline]
Deryugina, E.I., M.A. Bourdon, K. Jungwirth, J.W. Smith, and A.Y. Strongin. 2000. Functional activation of integrin vß3 in tumor cells expressing membrane-type 1 matrix metalloproteinase. Int. J. Cancer. 86:1523.[Medline]
Egeblad, M., and Z. Werb. 2002. New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer. 2:161174.[Medline]
Engsig, M.T., Q.-J. Chen, T.H. Vu, A.-C. Pedersen, B. Therrkidsen, L.R. Lund, K. Henriksen, T. Lenhard, N.T. Foged, Z. Werb, and J.-M. Delaisse. 2000. Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones. J. Cell Biol. 151:879889.
Fisher, C., S. Gilbertson-Beadling, E.A. Powers, G. Petzold, R. Poorman, and M.A. Mitchell. 1994. Interstitial collagenase is required for angiogenesis in vitro. Dev. Biol. 162:499510.[CrossRef][Medline]
Gálvez, B.G., S. Matías-Román, M. Yáñez-Mó, F. Sánchez-Madrid, and A.G. Arroyo. 2002. ECM regulates MT1-MMP localization with ß1 or vß3 integrins at distinct cell compartments modulating its internalization and activity on human endothelial cells. J. Cell Biol. 159:509521.
Guedez, L., A.M. Rivera, R. Salloum, M.L. Miller, J.J. Diegmueller, P.M. Bungam, and W.G. Stetler-Stevenson. 2003. Quantitative assessment of angiogenic responses by the directed in vivo angiogenesis assay. Am. J. Pathol. 162:14311439.
Haas, T.L., S.J. Davis, and J.A. Madri. 1998. Three-dimensional type I collagen lattices induce coordinate expression of matrix metalloproteinases MT1-MMP and MMP-2 in microvascular endothelial cells. J. Biol. Chem. 273:36043610.
Hamano, Y., M. Zeisberg, H. Sugimoto, J.C. Lively, Y. Maeshima, C. Yang, R.O. Hynes, Z. Werb, A. Sudhakar, and R. Kalluri. 2003. Physiological levels of tumstatin, a fragment of collagen IV 3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via
vß3 integrin. Cancer Cell. 3:589601.[Medline]
Hay, E.D. 1991. Cell Biology of Extracellular Matrix. Plenum Press, New York. 417 pp.
Heissig, B., K. Hattori, M. Friedrich, S. Rafii, and Z. Werb. 2003. Angiogenesis: vascular remodeling of the extracellular matrix involves metalloproteinases. Curr. Opin. Hematol. 10:136141.[CrossRef][Medline]
Hiraoka, N., E. Allen, I.J. Apel, M.R. Gyetko, and S.J. Weiss. 1998. Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins. Cell. 95:365377.[Medline]
Holmbeck, K., P. Bianco, J. Caterina, S. Yamada, M. Kromer, S.A. Kuznetsov, M. Mankani, P.G. Robey, A.R. Poole, I. Pidoux, et al. 1999. MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell. 99:8192.[Medline]
Hotary, K., E. Allen, A. Punturieri, I. Yana, and S.J. Weiss. 2000. Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3. J. Cell Biol. 149:13091323.
Hotary, K.B., I. Yana, F. Sabeh, X.-Y. Li, K. Holmbeck, H. Birkedal-Hansen, E.D. Allen, N. Hiraoka, and S.J. Weiss. 2002. Matrix metalloproteinases (MMPs) regulate fibrin-invasive activity via MT1-MMPdependent and independent processes. J. Exp. Med. 195:295308.
Hotary, K.B., E.D. Allen, P.C. Brooks, N.S. Datta, M.W. Long, and S.J. Weiss. 2003. Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell. 114:3345.[Medline]
Itoh, T., M. Tanioka, H. Yoshida, T. Yoshioka, H. Nishimoto, and S. Itohara. 1998. Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res. 58:10481051.[Abstract]
Kajita, M., Y. Itoh, T. Chiba, H. Mori, A. Okada, H. Kinoh, and M. Seiki. 2001. Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. J. Cell Biol. 153:893904.
Kheradmand, F., K. Rishi, and Z. Werb. 2002. Signaling through the EGF receptor controls lung morphogenesis in part by regulating MT1-MMP-mediated activation of gelatinase A/MMP2. J. Cell Sci. 115:839848.
Koivunen, E., W. Arap, H. Valtanen, A. Rainisalo, O.P. Medina, P. Heikkila, C. Kantor, C.G. Gahmberg, T. Salo, Y.T. Konttinen, et al. 1999. Tumor targeting with a selective gelatinase inhibitor. Nat. Biotechnol. 17:768774.[CrossRef][Medline]
Lafleur, M.A., M.M. Handsley, V. Knauper, G. Murphy, and D.R. Edwards. 2002. Endothelial tubulogenesis within fibrin gels specifically requires the activity of membrane-type-matrix metalloproteinases (MT-MMPs). J. Cell Sci. 115:34273438.
Lelongt, B., G. Trugnan, G. Murphy, and P.M. Ronco. 1997. Matrix metalloproteinases MMP2 and MMP9 are produced in early stages of kidney morphogenesis but only MMP9 is required for renal organogenesis in vitro. J. Cell Biol. 136:13631373.
Lubarsky, B., and M.A. Krasnow. 2003. Tube morphogenesis: making and shaping biological tubes. Cell. 112:1928.[Medline]
Lyden, D., A.Z. Young, D. Zagzag, W. Yan, W. Gerald, R. O'Reilly, B.L. Bader, R.O. Hynes, Y. Zhuang, K. Manova, and R. Benezra. 1999. Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature. 401:670677.[CrossRef][Medline]
Miralles, F., T. Battelino, P. Czernichow, and R. Scharfmann. 1998. TGF-ß plays a key role in morphogenesis of the pancreatic islets of Langerhans by controlling the activity of the matrix metalloproteinase MMP-2. J. Cell Biol. 143:827836.
Mori, H., T. Tomari, N. Koshikawa, M. Kajita, Y. Itoh, H. Sato, H. Tojo, I. Yana, and M. Seiki. 2002. CD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domain. EMBO J. 21:39493959.
Morita, Y., J. Yang, R. Gupta, K. Shimizu, E.A. Shelden, J. Endres, J.J. Mule, K.T. McDonagh, and D.A. Fox. 2001. Dendritic cells genetically engineered to express IL-4 inhibit murine collagen-induced arthritis. J. Clin. Invest. 107:12751284.
Murphy, H.S., N. Bakopoulos, M.K. Dame, J. Varani, and P.A. Ward. 1998. Heterogeneity of vascular endothelial cells: differences in susceptibility to neutrophil-mediated injury. Microvasc. Res. 56:203211.[CrossRef][Medline]
Nicosia, R.F., and J.A. Madri. 1987. The microvascular extracellular matrix. Developmental changes during angiogenesis in the aortic ring-plasma clot model. Am. J. Pathol. 128:7890.[Abstract]
Oh, J., R. Takahashi, E. Adachi, S. Kondo, S. Kuratomi, A. Noma, D.B. Alexander, H. Motoda, A. Okada, M. Seiki, et al. 2004. Mutations in two matrix metalloproteinase genes, MMP-2 and MT1-MMP, are synthetic lethal in mice. Oncogene. 23:50415048.[CrossRef][Medline]
Ohuchi, E., K. Imai, Y. Fujii, H. Sato, M. Seiki, and Y. Okada. 1997. Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. J. Biol. Chem. 272:24462451.
Pepper, M.S. 2001. Role of the matrix metalloproteinase and plasminogen activator-plasmin systems in angiogenesis. Arterioscler. Thromb. Vasc. Biol. 21:11041117.
Reynolds, L.E., L. Wyder, J.C. Lively, D. Tavema, S.D. Robinson, X. Huang, D. Sheppard, R.O. Hynes, and K.M. Hodivala-Dilke. 2002. Enhanced pathological angiogenesis in mice lacking ß3 integrin or ß3 and ß5 integrins. Nat. Med. 8:2734.[CrossRef][Medline]
Rolli, M., E. Fransvea, J. Pilch, A. Saven, and B. Felding-Habermann. 2003. Activated integrin vß3 cooperates with metalloproteinase MMP-9 in regulating migration of metastatic breast cancer cells. Proc. Natl. Acad. Sci. USA. 100:94829487.
Romer, J., T.H. Bugge, C. Pyke, L.R. Lund, M.J. Flick, J.L. Degen, and K. Dano. 1996. Impaired wound healing in mice with a disrupted plasminogen gene. Nat. Med. 2:287292.[Medline]
Seandel, M., K. Noack-Kunnmann, D. Zhu, R.T. Aimes, and J.P. Quigley. 2001. Growth factor-induced angiogenesis in vivo requires specific cleavage of fibrillar type I collagen. Blood. 97:23232332.
Seiki, M. 2002. The cell surface: the stage for matrix metalloproteinase regulation of migration. Curr. Opin. Cell Biol. 14:624632.[CrossRef][Medline]
Seo, D.-W., H. Li, L. Guedez, P.T. Wingfield, T. Diaz, R. Salloum, B.-Y. Wei, and W.G. Stetler-Stevenson. 2003. TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell. 114:171180.[CrossRef][Medline]
Shi, G.-P., G.K. Sukhova, M. Kuzuya, Q. Ye, J. Du, Y. Zhang, J.-H. Pan, M.L. Lu, X.W. Cheng, A. Iguchi, et al. 2003. Deficiency of the cysteine protease cathepsin S impairs microvessel growth. Circ. Res. 92:493500.
Silletti, S., T. Kessler, J. Goldberg, D.L. Boger, and D.A. Cheresh. 2001. Disruption of matrix metalloproteinase 2 binding to integrin vß3 by an organic molecule inhibits angiogenesis and tumor growth in vivo. Proc. Natl. Acad. Sci. USA. 98:119124.
Tournier, J.-M., M. Polette, J. Hinnrasky, J. Beck, Z. Werb, and C. Basbaum. 1994. Expression of gelatinase A, a mediator of extracellular matrix remodeling, by tracheal gland serous cells in culture and in vivo. J. Biol. Chem. 269:2545425464.
Toth, M., I. Chvyrkova, M.M. Bernardo, S. Hernandez-Barrantes, and R. Fridman. 2003. Pro-MMP-9 activation by the MT1-MMP/MMP-2 axis and MMP-3: role of TIMP-2 and plasma membranes. Biochem. Biophys. Res. Commun. 308:386395.[CrossRef][Medline]
Van Exan, R.J., and M.H. Hardy. 1984. The differentiation of the dermis in the laboratory mouse. Am. J. Anat. 169:149164.[Medline]
Wang, Q., P. Teder, N.P. Judd, P.W. Noble, and C.M. Doerschuk. 2002. CD44 deficiency leads to enhanced neutrophil migration and lung injury in Escherichia coli pneumonia in mice. Am. J. Pathol. 161:22192228.
Wiseman, B.S., M.D. Sternlicht, L.R. Lund, C.M. Alexander, J. Mott, M.J. Bissell, P. Soloway, S. Itohara, and Z. Werb. 2003. Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis. J. Cell Biol. 162:11231133.
Xu, J., E. Petitclerc, J.J. Kim, M. Hangai, S.M. Yuen, G.E. Davis, and P.C. Brooks. 2001. Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivo. J. Cell Biol. 154:10691079.
Yana, I., and S.J. Weiss. 2000. Regulation of membrane type-1 matrix metalloproteinase activation by proprotein convertases. Mol. Biol. Cell. 11:23872401.
Yu, Q., and I. Stamenkovic. 1999. Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev. 13:3548.
Zhou, Z., S.S. Apte, R. Soininen, R. Cao, G.Y. Baaklini, R.W. Rauser, J. Wang, Y. Cao, and K. Tryggvason. 2000. Impaired endothondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc. Natl. Acad. Sci. USA. 97:40524057.
Zhu, W.-H., X. Guo, S. Villaschi, and R.F. Nicosia. 2000. Regulation of vascular growth and regression by matrix metalloproteinases in the rat aorta model of angiogenesis. Lab. Invest. 80:545555.[Medline]