Stromal regulation of vessel stability by MMP14 and TGFbeta.
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 (TGFbeta(1)). 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 TGFbeta(1), 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 TGFbeta bioavailability are chronically elevated, or in mice that ectopically express TGFbeta 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 TGFbeta 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 TGFbeta 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.
Cancer Research Institute, University of California-San Francisco, 513 Parnassus Ave., San Francisco, CA 94143, USA.
Nor E
NE
Sounni
Kerstin
K
Dehne
Leon
L
van Kempen
Mikala
M
Egeblad
Nesrine I
NI
Affara
Ileana
I
Cuevas
Jane
J
Wiesen
Simon
S
Junankar
Lidiya
L
Korets
Jake
J
Lee
Jennifer
J
Shen
Charlotte J
CJ
Morrison
Christopher M
CM
Overall
Stephen M
SM
Krane
Zena
Z
Werb
Nancy
N
Boudreau
Lisa M
LM
Coussens
D000375:Aging / Q000473:pathology; D000818:Animals; D001808:Blood Vessels / Q000201:enzymology* / Q000473:pathology*; D024022:Fibrillar Collagens / Q000378:metabolism; D006706:Homeostasis; D053511:Matrix Metalloproteinase 14 / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009149:Mustard Plant; D010938:Plant Oils; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D012878:Skin Neoplasms / Q000098:blood supply / Q000473:pathology; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014655:Vascular Resistance
D024022:Fibrillar Collagens; D010938:Plant Oils; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse; D053511:Matrix Metalloproteinase 14; C027793:mustard oil