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Disease Models and Mechanisms

Year: 2010  |  Volume: 3  |  Issue: 5-6  |  Page No.: 317 - 332

Stromal regulation of vessel stability by MMP14 and TGF{beta}

N. E Sounni, K Dehne, L van Kempen, M Egeblad, N. I Affara, I Cuevas, J Wiesen, S Junankar, L Korets, J Lee, J Shen, C. J Morrison, C. M Overall, S. M Krane, Z Werb, N Boudreau and L. M. Coussens

Abstract

Nor E. Sounni, Kerstin Dehne, Leon van Kempen, Mikala Egeblad, Nesrine I. Affara, Ileana Cuevas, Jane Wiesen, Simon Junankar, Lidiya Korets, Jake Lee, Jennifer Shen, Charlotte J. Morrison, Christopher M. Overall, Stephen M. Krane, Zena Werb, Nancy Boudreau, and Lisa M. Coussens

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 (TGFβ1). Whereas plasma proteins rapidly extravasate out of vasculature in wild-type mice following acute damage, short-term treatment of mice in vivo with a broad-spectrum metalloproteinase inhibitor, neutralizing antibodies to TGFβ1, 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.

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