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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2015     Display Documents

ID: 711889.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2015
Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis
Authors:Li, W.; Li, Q.; Jiao, Y.; Qin, L.; Ali, R.; Zhou, J.; Ferruzzi, J.; Kim, R. W.; Geirsson, A.; Dietz, H. C.; Offermanns, S.; Humphrey, J. D.; Tellides, G.
Date of Publication (YYYY-MM-DD):2014-02
Title of Journal:J Clin Invest
Issue / Number:2
Start Page:755
End Page:767
Audience:Not Specified
Abstract / Description:TGF-beta is essential for vascular development; however, excess TGF-beta signaling promotes thoracic aortic aneurysm and dissection in multiple disorders, including Marfan syndrome. Since the pathology of TGF-beta overactivity manifests primarily within the arterial media, it is widely assumed that suppression of TGF-beta signaling in vascular smooth muscle cells will ameliorate aortic disease. We tested this hypothesis by conditional inactivation of Tgfbr2, which encodes the TGF-beta type II receptor, in smooth muscle cells of postweanling mice. Surprisingly, the thoracic aorta rapidly thickened, dilated, and dissected in these animals. Tgfbr2 disruption predictably decreased canonical Smad signaling, but unexpectedly increased MAPK signaling. Type II receptor-independent effects of TGF-beta and pathological responses by nonrecombined smooth muscle cells were excluded by serologic neutralization. Aortic disease was caused by a perturbed contractile apparatus in medial cells and growth factor production by adventitial cells, both of which resulted in maladaptive paracrine interactions between the vessel wall compartments. Treatment with rapamycin restored a quiescent smooth muscle phenotype and prevented dissection. Tgfbr2 disruption in smooth muscle cells also accelerated aneurysm growth in a murine model of Marfan syndrome. Our data indicate that basal TGF-beta signaling in smooth muscle promotes postnatal aortic wall homeostasis and impedes disease progression.
Free Keywords:Animals; Aorta, Thoracic/metabolism/*pathology; Blood Pressure; Cell Proliferation; Collagen/chemistry; Disease Progression; Green Fluorescent Proteins/metabolism; Homeostasis; Immunohistochemistry; MAP Kinase Signaling System; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Muscle, Smooth, Vascular/*metabolism; Phenotype; Protein-Serine-Threonine Kinases/*metabolism; Receptors, Transforming Growth Factor beta/*metabolism; Sirolimus/chemistry; Smad Proteins/metabolism; Transforming Growth Factor beta/metabolism
External Publication Status:published
Document Type:Article
Communicated by:MPI für Herz- und Lungenforschung
Affiliations:MPI für physiologische und klinische Forschung
Identifiers:ISSN:1558-8238 (Electronic) 0021-9738 (Linking) %R 10.1172/JCI69942
URL:http://www.ncbi.nlm.nih.gov/pubmed/24401272 %^ 143...
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