Stromal regulation of vessel stability by MMP14 and TGFbeta

Sounni, N. E., Dehne, K., Van Kempen, L., Egeblad, M., Affara, N. I., Cuevas, I., Wiesen, J., Junankar, S., Korets, L., Lee, J., Shen, J., Morrison, C. J., Overall, C. M., Krane, S. M., Werb, Z., Boudreau, N., Coussens, L. M. (March 2010) Stromal regulation of vessel stability by MMP14 and TGFbeta. Disease Models and Mechanisms, 3 (5-6). pp. 317-332. ISSN 17548403 (ISSN)

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URL: http://www.ncbi.nlm.nih.gov/pubmed/20223936
DOI: 10.1242/dmm.003863

Abstract

Innate regulatory networks within organs maintain tissue homeostasis and facilitate rapid responses to damage. We identified a novel pathway regulating vessel stability in tissues that involves matrix metalloproteinase 14 (MMP14) and transforming growth factor beta 1 (TGFβ<sub>1</sub>). Whereas plasma proteins rapidly extravasate out of vasculature in wild-type mice following acute damage, short-term treatment of mice in vivo with a broadspectrum metalloproteinase inhibitor, neutralizing antibodies to TGFβ<sub>1</sub>, or an activin-like kinase 5 (ALK5) inhibitor significantly enhanced vessel leakage. By contrast, in a mouse model of age-related dermal fibrosis, where MMP14 activity and TGFβ bioavailability are chronically elevated, or in mice that ectopically express TGFβ in the epidermis, cutaneous vessels are resistant to acute leakage. Characteristic responses to tissue damage are reinstated if the fibrotic mice are pretreated with metalloproteinase inhibitors or TGFβ signaling antagonists. Neoplastic tissues, however, are in a constant state of tissue damage and exhibit altered hemodynamics owing to hyperleaky angiogenic vasculature. In two distinct transgenic mouse tumor models, inhibition of ALK5 further enhanced vascular leakage into the 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 TGFβ that mediates vessel stability and vascular response to tissue injury. Antagonists of this pathway could be therapeutically exploited to improve the delivery of therapeutics or molecular contrast agents into tissues where chronic damage or neoplastic disease limits their efficient delivery.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > metalloproteinases
organism description > animal > mammal > rodent > mouse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:
Communities: CSHL labs > Egeblad lab
Depositing User: CSHL Librarian
Date: 11 March 2010
Date Deposited: 19 Oct 2011 14:31
Last Modified: 26 Apr 2013 16:56
PMCID: PMC2860851
Related URLs:
URI: http://repository.cshl.edu/id/eprint/15532

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