vascular leakage; TGFbeta; MMP14/MT1-MMP; extracellular matrix; type I collagen
Abstract :
[en] Innate regulatory networks within organs maintain tissue homeostasis and facilitate rapid responses to damage. We identified a novel pathway regulating vessel stability in tissues involving matrix metalloproteinase 14 (MMP14) and transforming growth factor beta (TGFbeta)1. Whereas plasma proteins rapidly extravasate out of vasculature in wildtype mice following acute damage, short-term treatment of mice in vivo with a broad-spectrum metalloproteinase inhibitor, neutralizing antibodies to TGFbeta1 or an ALK5 inhibitor significantly enhanced vessel leakage. In contrast, in a mouse model of age-related dermal fibrosis where MMP14 activity and TGFbeta bioavailability are chronically elevated, or in mice that ectopically express TGFbeta in epidermis, cutaneous vessels are resistant to acute leakage. Characteristic responses to tissue damage are reinstated if fibrotic mice are pre-treated with metalloproteinase inhibitors or TGFbeta signaling antagonists. Neoplastic tissues on the other hand are in a constant state of tissue damage and exhibit altered hemodynamics due to hyperleaky angiogenic vasculature. In two distinct transgenic mouse tumor models, inhibition of ALK5 further enhanced vascular leakage into interstitium and facilitated increased delivery of high molecular weight compounds into premalignant tissue and tumors. Taken together, these data define a central pathway involving MMP14 and TGFbeta that mediate vessel stability and vascular response to tissue injury. Antagonists of this pathway could be therapeutically exploited to improve delivery of therapeutics or molecular contrast agents into tissues where chronic damage or neoplastic disease limits their efficient delivery.
Disciplines :
Biotechnology
Author, co-author :
Sounni, Nor Eddine ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Stromal regulation of vessel stability by MMP14 and TGFbeta.
Publication date :
May 2010
Journal title :
Disease Models and Mechanisms
ISSN :
1754-8411
eISSN :
1754-8403
Publisher :
The Company of Biologists Ltd, Cambridge, United Kingdom
Volume :
3
Pages :
317-332
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
CAC - Centre anticancéreux près l'Université de Liège asbl [BE] NIH grants CA72006, AI053194 and CA105379 (ZW and ME), CA72006, CA98075, CA94168 National Technology Center for Networks and Pathways (U54 RR020843) Department of Defense Breast Cancer Research Program Era of Hope Scholar Award (W81XWH-06-1-0416)
Commentary :
TRANSLATIONAL IMPACT
Clinical issue
In patients with locally advanced solid tumors, the first-line treatment is often neo-adjuvant or pre-operative chemotherapy, which helps shrink tumors before surgery, allowing for more conservative surgical approaches and reducing the potential for developing systemic disease. However, despite aggressive chemotherapy, long-term survival for many patients remains poor, in part owing to limitations with the targeting and accumulation of cytotoxic drugs in tumor tissue.
The vasculature of solid tumors is abnormal, both in terms of vessel architecture and the dynamics of blood flow. Permeable heterogeneous vessel walls allow the leakage of proteins and fluid that, coupled with the inefficiency of lymphatic drainage, could be exploited to develop novel, enhanced drug delivery strategies that are therapeutically selective and improve clinical outcome.
Results
This work describes a previously unappreciated role for transforming growth factor beta (TGFbeta) in regulating vascular stability and vessel permeability in solid tumors. Using mouse models, the authors demonstrate an endogenous pathway that regulates normal vascular permeability, which is controlled by perivascular collagen, the metalloproteinase enzyme MMP14, and TGFbeta. In wild-type mice, inhibitors of either MMP14 or TGFbeta signaling induce blood vessel permeability. Conversely, enhanced MMP14 or TGFbeta activity in the mouse epidermis decreases leakage across cutaneous vessels. This pathway remains functional during tumor progression, as acute blockade of either MMP14 or TGFbeta signaling transiently alters vessel stability, ‘opening’ vascular beds and promoting intravenous delivery of high molecular weight compounds to the tumor.
Implications and future directions
The delivery of standard therapeutic agents or diagnostic molecular imaging
agents to tumor tissue may be enhanced by transient blockade of the TGFbeta
pathway. If so, this could advance disease therapy and/or diagnostic imaging,
not only in cancer medicine, but also in fibrotic disorders such as scleroderma
and kidney failure.
Press releases related to this work:
Drug delivery to solid tumors can be enhanced by transient breakdown of blood vessel walls
Genetic Engineering and Biotechnology news: Mar 10, 2010
http://www.genengnews.com/industry-updates/exploiting-the-architecture-of-cancers-may-lead-to-their-destruction/77453039/
Exploiting the architecture of cancers may lead to their destruction
Drug delivery to solid tumors can be enhanced by transient breakdown of blood vessel walls
Public release date: 10-Mar-2010
http://www.eurekalert.org/pub_releases/2010-03/tcob-eta030410.php
Destroying Cancers By Exploiting Their Architecture
Cancer/Oncology news Article Date: 11 Mar 2010
http://www.medicalnewstoday.com/articles/181964.php
Destroying Cancers By Exploiting Their Architecture
Medical news Date: 2010-03-11
http://www.medicalnewstody.com/Other_health_news/1967.html
Exploiting the architecture of cancers may lead to their destruction
The Company of Biologists - 10 Mar 2010
http://www.firstscience.com/home/news/breaking-news-all-topics/exploiting-the-architecture-of-cancers-may-lead-to-their-destruction-page-2-1_80558.html
Leakier Tumor Vessels Enhance Drug Delivery
Molecules that make blood vessels more permeable might boost chemotherapeutics.
Technology review: Friday, March 12, 2010
http://www.technologyreview.com/printer_friendly_article.aspx?id=24757&channel=biomedicine§ion
Exploiting the Architecture of Cancers May Lead to Their Destruction
ScienceDaily: Mar. 13, 2010
http://www.sciencedaily.com/releases/2010/03/100310162825.htm
Exploiting the Architecture of Cancers May Lead to Their Destruction
Brain Tumor survivor Posted: Sun Mar 14, 2010 8:33 am
http://www.btsurvivor.com/bb/viewtopic.php?p=4391&sid=d04fc97e24aed5f1f6b3480472c0b348
Abe, M., Harpel, J. G., Metz, C. N., Nunes, I., Loskutoff, D. J. and Rifkin, D. B. (1994). An assay for transforming growth factor-beta using cells transfected with a plasminogen activator inhibitor-1 promoter-luciferase construct. Anal. Biochem. 216, 276-284. (Pubitemid 24076008)
Alfranca, A., Lopez-Oliva, J. M., Genis, L., Lopez-Maderuelo, D., Mirones, I., Salvado, D., Quesada, A. J., Arroyo, A. G. and Redondo, J. M. (2008). PGE2 induces angiogenesis via MT1-MMP-mediated activation of the TGFbeta/Alk5 signaling pathway. Blood 112, 1120-1128.
Annes, J. P., Munger, J. S. and Rifkin, D. B. (2003). Making sense of latent TGFbeta activation. J. Cell Sci. 116, 217-224.
Araya, J., Cambier, S., Morris, A., Finkbeiner, W. and Nishimura, S. L. (2006). Integrin-mediated transforming growth factor-{beta} activation regulates homeostasis of the pulmonary epithelial-mesenchymal trophic unit. Am. J. Pathol. 169, 405-415. (Pubitemid 44156303)
Balbin, M., Fueyo, A., Tester, A. M., Pendas, A. M., Pitiot, A. S., Astudillo, A., Overall, C. M., Shapiro, S. D. and Lopez-Otin, C. (2003). Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nat. Genet. 35, 252-257. (Pubitemid 37363179)
Bergers, G., Brekken, R., McMahon, G., Vu, T. H., Itoh, T., Tamaki, K., Tanzawa, K., Thorpe, P., Itohara, S., Werb, Z. et al. (2000). Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol. 2, 737-744.
Bergman, I. and Loxley, R. (1963). Two improved and simplified methods for the spectrophotometric determination of hydroxyproline. Anal. Chem. 35, 1961-1965.
Bernardo, M. M. and Fridman, R. (2003). TIMP-2 (tissue inhibitor of metalloproteinase-2) regulates MMP-2 (matrix metalloproteinase-2) activity in the extracellular environment after pro-MMP-2 activation by MT1 (membrane type 1)-MMP. Biochem. J. 374, 739-745.
Bhushan, M., Young, H. S., Brenchley, P. E. and Griffiths, C. E. (2002). Recent advances in cutaneous angiogenesis. Br. J. Dermatol. 147, 418-425.
Brown, E., McKee, T., diTomaso, E., Pluen, A., Seed, B., Boucher, Y. and Jain, R. K. (2003). Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation. Nat. Med. 9, 796-800.
Cambier, S., Gline, S., Mu, D., Collins, R., Araya, J., Dolganov, G., Einheber, S., Boudreau, N. and Nishimura, S. L. (2005). Integrin alpha(v)beta8-mediated activation of transforming growth factor-beta by perivascular astrocytes: an angiogenic control switch. Am. J. Pathol. 166, 1883-1894. (Pubitemid 40734410)
Cao, T., He, W., Roop, D. R. and Wang, X. J. (2002). K14-GLp65 transactivator induces transgene expression in embryonic epidermis. Genesis 32, 189-190. (Pubitemid 34211737)
Coussens, L. M., Hanahan, D. and Arbeit, J. M. (1996). Genetic predisposition and parameters of malignant progression in K14- HPV16 transgenic mice. Am. J. Pathol. 149, 1899-1917. (Pubitemid 26415210)
Dallas, S. L., Rosser, J. L., Mundy, G. R. and Bonewald, L. F. (2002). Proteolysis of latent transforming growth factor-beta (TGF-beta)-binding protein-1 by osteoclasts. A cellular mechanism for release of TGF-beta from bone matrix. J. Biol. Chem. 277, 21352-21360.
Dickson, M. C., Martin, J. S., Cousins, F. M., Kulkarni, A. B., Karlsson, S. and Akhurst, R. J. (1995). Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development 121, 1845-1854.
Drab, M., Verkade, P., Elger, M., Kasper, M., Lohn, M., Lauterbach, B., Menne, J., Lindschau, C., Mende, F., Luft, F. C. et al. (2001). Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 293, 2449-2452. (Pubitemid 32917325)
Dumont, N. and Arteaga, C. L. (2003). Targeting the TGF beta signaling network in human neoplasia. Cancer Cell 3, 531-536. (Pubitemid 36808648)
Egeblad, M., Shen, H. C., Behonick, D. J., Wilmes, L., Eichten, A., Korets, L. V., Kheradmand, F., Werb, Z. and Coussens, L. M. (2007). Type I collagen is a genetic modifier of matrix metalloproteinase 2 in murine skeletal development. Dev. Dyn. 236, 1683-1693. (Pubitemid 46932371)
Egeblad, M., Ewald, A. J., Askautrud, H. A., Truitt, M. L., Welm, B. E., Bainbridge, E., Peeters, G., Krummel, M. F. and Werb, Z. (2008). Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy. Dis. Model. Mech. 1, 155-167.
Eichten, A. E., Shen, H.-C. J. and Coussens, L. M. (2005). Three-dimensional visualization of blood and lymphatic vasculature in tissue whole mounts using confocal microscopy. In Current Protocols in Cytometry (ed. J. P. Robinson), pp. 12.15.11-12.15.11. New Jersey: John Wiley & Sons, Inc.
Eichten, A. E., Hyun, W. C. and Coussens, L. M. (2007). Distinctive features of angiogenesis and lymphangiogenesis determine their functionality during de novo tumor development. Cancer Res. 67, 5211-5220.
Feng, D., Nagy, J. A., Hipp, J., Pyne, K., Dvorak, H. F. and Dvorak, A. M. (1997). Reinterpretation of endothelial cell gaps induced by vasoactive mediators in guineapig, mouse and rat: many are transcellular pores. J. Physiol. 504, 747-761. (Pubitemid 27493871)
Feng, D., Nagy, J. A., Dvorak, H. F. and Dvorak, A. M. (2002). Ultrastructural studies define soluble macromolecular, particulate, and cellular transendothelial cell pathways in venules, lymphatic vessels, and tumor-associated microvessels in man and animals. Microsc. Res. Tech. 57, 289-326. (Pubitemid 34579214)
Gade, T. P., Buchanan, I. M., Motley, M. W., Mazaheri, Y., Spees, W. M. and Koutcher, J. A. (2009). Imaging intratumoral convection: pressure-dependent enhancement in chemotherapeutic delivery to solid tumors. Clin. Cancer Res. 15, 247-255.
Galardy, R. E., Grobelny, D., Foellmer, H. G. and Fernandez, L. A. (1994). Inhibition of angiogenesis by the matrix metalloprotease inhibitor N-[2R-2-(hydroxamidocarbonymethyl)-4-methylpentanoyl)]-L-tryptophan methylamide. Cancer Res. 54, 4715-4718. (Pubitemid 24276500)
Gleizes, P. E. and Rifkin, D. B. (1999). Activation of latent TGF-beta. A required mechanism for vascular integrity. Pathol. Biol. (Paris) 47, 322-329.
Guy, C. T., Cardiff, R. D. and Muller, W. J. (1992). Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol. Cell. Biol. 12, 954-961.
Haas, T. L., Stitelman, D., Davis, S. J., Apte, S. S. and Madri, J. A. (1999). Egr-1 mediates extracellular matrix-driven transcription of membrane type 1 matrix metalloproteinase in endothelium. J. Biol. Chem. 274, 22679-22685. (Pubitemid 129529289)
Hashizume, H., Baluk, P., Morikawa, S., McLean, J. W., Thurston, G., Roberge, S., Jain, R. K. and McDonald, D. M. (2000). Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 156, 1363-1380. (Pubitemid 30660013)
Heldin, C. H., Rubin, K., Pietras, K. and Ostman, A. (2004). High interstitial fluid pressure-an obstacle in cancer therapy. Nat. Rev. Cancer 4, 806-813. (Pubitemid 39331152)
Herron, G. S., Werb, Z., Dwyer, K. and Banda, M. J. (1986a). Secretion of metalloproteinases by stimulated capillary endothelial cells. I. Production of procollagenase and prostromelysin exceeds expression of proteolytic activity. J. Biol. Chem. 261, 2810-2813. (Pubitemid 17218296)
Herron, G. S., Banda, M. J., Clark, E. J., Gavrilovic, J. and Werb, Z. (1986b). Secretion of metalloproteinases by stimulated capillary endothelial cells. II. Expression of collagenase and stromelysin activities is regulated by endogenous inhibitors. J. Biol. Chem. 261, 2814-2818. (Pubitemid 17218297)
Hirschi, K. K., Rohovsky, S. A. and D'Amore, P. A. (1998). PDGF, TGF-beta, and heterotypic cell-cell interactions mediate endothelial cell-induced recruitment of 10T1/2 cells and their differentiation to a smooth muscle fate. J. Cell Biol. 141, 805-814.
Inoue, H., Asaka, T., Nagata, N. and Koshihara, Y. (1997). Mechanism of mustard oilinduced skin inflammation in mice. Eur. J. Pharmacol. 333, 231-240. (Pubitemid 27387396)
Ishida, W., Mori, Y., Lakos, G., Sun, L., Shan, F., Bowes, S., Josiah, S., Lee, W. C., Singh, J., Ling, L. E. et al. (2006). Intracellular TGF-beta receptor blockade abrogates Smad-dependent fibroblast activation in vitro and in vivo. J. Invest. Dermatol. 126, 1733-1744. (Pubitemid 44086506)
Itoh, T., Ikeda, T., Gomi, H., Nakao, S., Suzuki, T. and Itohara, S. (1997). Unaltered secretion of beta-amyloid precursor protein in gelatinase A (matrix metalloproteinase 2)-deficient mice. J. Biol. Chem. 272, 22389-22392. (Pubitemid 27386043)
Jacob, M. P., Badier-Commander, C., Fontaine, V., Benazzoug, Y., Feldman, L. and Michel, J. B. (2001). Extracellular matrix remodeling in the vascular wall. Pathol. Biol. (Paris) 49, 326-332. (Pubitemid 32494258)
Kano, M. R., Bae, Y., Iwata, C., Morishita, Y., Yashiro, M., Oka, M., Fujii, T., Komuro, A., Kiyono, K., Kaminishi, M. et al. (2007). Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-beta signaling. Proc. Natl. Acad. Sci. USA 104, 3460-3465. (Pubitemid 46364181)
Lammerts, E., Roswall, P., Sundberg, C., Gotwals, P. J., Koteliansky, V. E., Reed, R. K., Heldin, N. E. and Rubin, K. (2002). Interference with TGF-beta1 and -beta3 in tumor stroma lowers tumor interstitial fluid pressure independently of growth in experimental carcinoma. Int. J. Cancer 102, 453-462. (Pubitemid 35315998)
Lehti, K., Allen, E., Birkedal-Hansen, H., Holmbeck, K., Miyake, Y., Chun, T. H. and Weiss, S. J. (2005). An MT1-MMP-PDGF receptor-beta axis regulates mural cell investment of the microvasculature. Genes Dev. 19, 979-991. (Pubitemid 40548065)
Liu, X., Wu, H., Byrne, M., Jeffrey, J., Krane, S. and Jaenisch, R. (1995). A targeted mutation at the known collagenase cleavage site in mouse type I collagen impairs tissue remodeling. J. Cell Biol. 130, 227-237.
Loeffler, M., Kruger, J. A., Niethammer, A. G. and Reisfeld, R. A. (2006). Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J. Clin. Invest. 116, 1955-1962. (Pubitemid 44033319)
Lu, S. L., Reh, D., Li, A. G., Woods, J., Corless, C. L., Kulesz-Martin, M. and Wang, X. J. (2004). Overexpression of transforming growth factor beta1 in head and neck epithelia results in inflammation, angiogenesis, and epithelial hyperproliferation. Cancer Res. 64, 4405-4410. (Pubitemid 38856909)
Madri, J. A., Bell, L. and Merwin, J. R. (1992). Modulation of vascular cell behavior by transforming growth factors beta. Mol. Reprod. Dev. 32, 121-126.
Maniatis, T., Fritsch, E. F. and Sambrook, J. (1982). Molecular cloning: A laboratory manual. Cold Spring Harbor: Cold Spring Harbor Laboratory Press.
McDonald, D. M. and Baluk, P. (2002). Significance of blood vessel leakiness in cancer. Cancer Res. 62, 5381-5385. (Pubitemid 35024617)
McKee, T. D., Pluen, A., Boucher, Y., Ramanujan, S., Unemori, E., Seed, B. and Jain, R. K. (2001). Relaxin increases the transport of large molecules in high collagen content tumors. Proc. Am. Assoc. Cancer Res. 42, 30.
McKee, T. D., Grandi, P., Mok, W., Alexandrakis, G., Insin, N., Zimmer, J. P., Bawendi, M. G., Boucher, Y., Breakefield, X. O. and Jain, R. K. (2006). Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector. Cancer Res. 66, 2509-2513.
Mehta, D. and Malik, A. B. (2006). Signaling mechanisms regulating endothelial permeability. Physiol. Rev. 86, 279-367.
Miles, A. A. and Miles, E. M. (1952). Vascular reactions to histamine, histamineliberator and leukotaxine in the skin of guinea pigs. J. Physiol. 118, 228-257.
Miller, E. J. and Rhodes, R. K. (1982). Preparation and characterization of the different types of collagen. Methods Enzymol. 82, 33-64.
Minchinton, A. I. and Tannock, I. F. (2006). Drug penetration in solid tumours. Nat. Rev. Cancer 6, 583-592.
Mott, J. D. and Werb, Z. (2004). Regulation of matrix biology by matrix metalloproteinases. Curr. Opin. Cell Biol. 16, 558-564.
Mu, D., Cambier, S., Fjellbirkeland, L., Baron, J. L., Munger, J. S., Kawakatsu, H., Sheppard, D., Broaddus, V. C. and Nishimura, S. L. (2002). The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1. J. Cell Biol. 157, 493-507. (Pubitemid 34839812)
Neptune, E. R., Frischmeyer, P. A., Arking, D. E., Myers, L., Bunton, T. E., Gayraud, B., Ramirez, F., Sakai, L. Y. and Dietz, H. C. (2003). Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat. Genet. 33, 407-411. (Pubitemid 36278859)
Overall, C. M. (2001). Matrix metalloproteinase substrate binding domains, modules and exosites. Overview and experimental strategies. Methods Mol. Biol. 151, 79-120.
Padua, D., Zhang, X. H., Wang, Q., Nadal, C., Gerald, W. L., Gomis, R. R. and Massague, J. (2008). TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133, 66-77. (Pubitemid 351442989)
Page, R. C. and Schroeder, H. E. (1982). Periodontitiis in humans. In Periodontitia in Man and Other Animals: A Comparative Review, pp. 5-57. Basel, Switzerland: Karger.
Page-McCaw, A., Ewald, A. J. and Werb, Z. (2007). Matrix metalloproteinases and the regulation of tissue remodelling. Nat. Rev. Mol. Cell Biol. 8, 221-233. (Pubitemid 46310551)
Parikh, S. M., Mammoto, T., Schultz, A., Yuan, H. T., Christiani, D., Karumanchi, S. A. and Sukhatme, V. P. (2006). Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Med. 3, e46.
Park, S. O., Lee, Y. J., Seki, T., Hong, K. H., Fliess, N., Jiang, Z., Park, A., Wu, X., Kaartinen, V., Roman, B. L. et al. (2008). ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2. Blood 111, 633-642.
Pepper, M. S. (1997). Transforming growth factor-beta: vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev. 8, 21-43.
Pittet, J. F., Griffiths, M. J., Geiser, T., Kaminski, N., Dalton, S. L., Huang, X., Brown, L. A., Gotwals, P. J., Koteliansky, V. E., Matthay, M. A. et al. (2001). TGF-beta is a critical mediator of acute lung injury. J. Clin. Invest. 107, 1537-1544. (Pubitemid 32574640)
Pluen, A., Boucher, Y., Ramanujan, S., McKee, T. D., Gohongi, T., di Tomaso, E., Brown, E. B., Izumi, Y., Campbell, R. B., Berk, D. A. et al. (2001). Role of tumor-host interactions in interstitial diffusion of macromolecules: cranial vs. subcutaneous tumors. Proc. Natl. Acad. Sci. USA 98, 4628-4633. (Pubitemid 32295027)
Predescu, D., Predescu, S. and Malik, A. B. (2002). Transport of nitrated albumin across continuous vascular endothelium. Proc. Natl. Acad. Sci. USA 99, 13932-13937. (Pubitemid 35215483)
Ronaldson, P. T., Demarco, K. M., Sanchez-Covarrubias, L., Solinsky, C. M. and Davis, T. P. (2009). Transforming growth factor-beta signaling alters substrate permeability and tight junction protein expression at the blood-brain barrier during inflammatory pain. J. Cereb. Blood Flow Metab. 29, 1084-1098.
Roviezzo, F., Tsigkos, S., Kotanidou, A., Bucci, M., Brancaleone, V., Cirino, G. and Papapetropoulos, A. (2005). Angiopoietin-2 causes inflammation in vivo by promoting vascular leakage. J. Pharmacol. Exp. Ther. 314, 738-744. (Pubitemid 41043857)
Sato, Y. (1995). Activation of latent TGF-beta at the vascular wall-roles of endothelial cells and mural pericytes or smooth muscle cells. J. Atheroscler. Thromb. 2, 24-29.
Seki, T., Yun, J. and Oh, S. P. (2003). Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling. Circ. Res. 93, 682-689. (Pubitemid 37222165)
Seki, T., Hong, K. H. and Oh, S. P. (2006). Nonoverlapping expression patterns of ALK1 and ALK5 reveal distinct roles of each receptor in vascular development. Lab. Invest. 86, 116-129. (Pubitemid 43117592)
Sounni, N. E., Devy, L., Hajitou, A., Frankenne, F., Munaut, C., Gilles, C., Deroanne, C., Thompson, E. W., Foidart, J. M. and Noel, A. (2002). MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression. FASEB J. 16, 555-564. (Pubitemid 34273239)
Stickens, D., Behonick, D. J., Ortega, N., Heyer, B., Hartenstein, B., Yu, Y., Fosang, A. J., Schorpp-Kistner, M., Angel, P. and Werb, Z. (2004). Altered endochondral bone development in matrix metalloproteinase 13-deficient mice. Development 131, 5883-5895. (Pubitemid 40123905)
Su, G., Hodnett, M., Wu, N., Atakilit, A., Kosinski, C., Godzich, M., Huang, X. Z., Kim, J. K., Frank, J. A., Matthay, M. A. et al. (2007). Integrin alphavbeta5 regulates lung vascular permeability and pulmonary endothelial barrier function. Am. J. Respir. Cell Mol. Biol. 36, 377-386. (Pubitemid 46365289)
Susic, D. (2007). Cross-link breakers as a new therapeutic approach to cardiovascular disease. Biochem. Soc. Trans. 35, 853-856. (Pubitemid 350206381)
Tam, E. M., Wu, Y. I., Butler, G. S., Stack, M. S. and Overall, C. M. (2002). Collagen binding properties of the membrane type-1 matrix metalloproteinase (MT1-MMP) hemopexin C domain. The ectodomain of the 44-kDa autocatalytic product of MT1-MMP inhibits cell invasion by disrupting native type I collagen cleavage. J. Biol. Chem. 277, 39005-39014.
Tam, E. M., Morrison, C. J., Wu, Y., Stack, M. S. and Overall, C. M. (2004). Membrane protease proteomics: Isotope-coded affinity tag MS identification of undescribed MT1-matrix metalloproteinase substrates. PNAS 101, 6917-6922. (Pubitemid 38596418)
Thurston, G., Baluk, P., Hirata, A. and McDonald, D. M. (1996). Permeability-related changes revealed at endothelial cell borders in inflamed venules by lectin binding. Am. J. Physiol. 271, 2547-2562. (Pubitemid 27034427)
Thurston, G., Murphy, T. J., Baluk, P., Lindsey, J. R. and McDonald, D. M. (1998). Angiogenesis in mice with chronic airway inflammation: strain-dependent differences. Am. J. Pathol. 153, 1099-1112. (Pubitemid 28465833)
Tuxhorn, J. A., McAlhany, S. J., Yang, F., Dang, T. D. and Rowley, D. R. (2002). Inhibition of transforming growth factor-beta activity decreases angiogenesis in a human prostate cancer-reactive stroma xenograft model. Cancer Res. 62, 6021-6025. (Pubitemid 35244446)
Verbeek, M. M., Otte-Holler, I., Wesseling, P., Ruiter, D. J. and de Waal, R. M. (1994). Induction of alpha-smooth muscle actin expression in cultured human brain pericytes by transforming growth factor-beta 1. Am. J. Pathol. 144, 372-382. (Pubitemid 2041437)
Vinals, F. and Pouyssegur, J. (2001). Transforming growth factor beta1 (TGF-beta1) promotes endothelial cell survival during in vitro angiogenesis via an autocrine mechanism implicating TGF-alpha signaling. Mol. Cell. Biol. 21, 7218-7230. (Pubitemid 32953476)
Wang, M., Zhao, D., Spinetti, G., Zhang, J., Jiang, L. Q., Pintus, G., Monticone, R. and Lakatta, E. G. (2006). Matrix metalloproteinase 2 activation of transforming growth factor-beta1 (TGF-beta1) and TGF-beta1-type II receptor signaling within the aged arterial wall. Arterioscler. Thromb. Vasc. Biol. 26, 1503-1509. (Pubitemid 44288975)
Werb, Z. (1997). ECM and cell surface proteolysis: regulating cellular ecology. Cell 91, 439-442.
Woessner, J. F. (1961). The determination of hydroxyproline in tissue and protein samples containing small portions of this imino acid. Arch. Biochem. Biophys 93, 440-447.
Yamamoto, T., Takagawa, S., Katayama, I. and Nishioka, K. (1999). Anti-sclerotic effect of transforming growth factor-beta antibody in a mouse model of bleomycininduced scleroderma. Clin. Immunol. 92, 6-13. (Pubitemid 29315981)
Yan, Q. and Sage, E. H. (1998). Transforming growth factor-beta1 induces apoptotic cell death in cultured retinal endothelial cells but not pericytes: association with decreased expression of p21waf1/cip1. J. Cell Biochem. 70, 70-83. (Pubitemid 28310921)
Yu, Q. and Stamenkovic, I. (2000). Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 14, 163-176. (Pubitemid 30070982)
Zheng, T., Zhu, Z., Wang, Z., Homer, R. J., Ma, B., Riese, R. J., Jr, Chapman, H. A., Jr, Shapiro, S. D. and Elias, J. A. (2000). Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsin-dependent emphysema. J. Clin. Invest. 106, 1081-1093.
Zhou, Z., Apte, S. S., Soininen, R., Cao, R., Baaklini, G. Y., Rauser, R. W., Wang, J., Cao, Y. and Tryggvason, K. (2000). Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc. Natl. Acad. Sci. USA 97, 4052-4057. (Pubitemid 30226085)
