Marfan syndrome (MFS) is a common disorder caused by mutations in the gene encoding the matrix protein fibrillin-1. Our prior work has shown that many manifestations of MFS, including aortic aneurysm, valve disease, emphysema and skeletal muscle myopathy, are caused by excessive activation of and signaling by the TGF beta family of growth factors and can be attenuated by TGFbeta blockade in mouse models. The prevailing view has been that MFS manifests abnormal behaviors of "normal" cells due to alterations in their extracellular environment. We now present evidence for "abnormal" cells within the aortic wall of adult MFS mice that have undergone a TGFbeta-dependent permanent transition in identity and character during early development due to a process termed endothelial-to-mesenchymal transition (EnMT). After transition, resulting myofibroblasts exhibit many deleterious behaviors including high TGFbeta signaling, angiotensin II (Angll)-dependent fibrosis, and high expression of matrix-degrading enzymes. The major hypotheses to be tested in this work are that EnMT-derived cells drive progression of disease and that EnMT continues to populate the ascending aorta during postnatal life in disease states. Using mouse models, we will determine the pathways that drive EnMT in the aorta of fibrillin-1 deficient mice and will purify EnMT-derived cells, allowing identification of their deleterious behaviors and exploration of strategies to tame them. Currently, we can envision at least 9 different therapeutic agents that will theoretically prevent ongoing EnMT and/or modulate the nonproductive performance of myofibroblasts resident within the aortic wall at the time of initiation of treatment. These will be tested in genetically defined and validated mouse models of MFS. Remarkably, a number of these agents are already in clinical use for other indications, suggesting the potential for rapid translation to people with MFS. Our current data suggest a developmentally-imposed fixed alteration in cellular identify in the prediposition for apparently acquired late-onset phenotypes in MFS, This paradigm represents a novel way of thinking about genetic predisposition, aids in the elucidation of therapeutic limitations and opportunities, and will likely prove relevant to other conditions.

Public Health Relevance

This work will explore the basic mechanisms driving aortic aneurysm, a condition responsible for the death of 1-2% of individuals in industrialized countries. There is high potential that this work will derive novel therapeutic strategies for Marfan syndrome, and that these insights will prove relevant to other presentations of aortic aneurysm.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZAR1-MLB-F)
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Icahn School of Medicine at Mount Sinai
New York
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Cook, Jason R; Ramirez, Francesco (2014) Clinical, diagnostic, and therapeutic aspects of the Marfan syndrome. Adv Exp Med Biol 802:77-94
Dietz, Harry (2014) A healthy tension in translational research. J Clin Invest 124:1425-9
Liu, Dongyan; Wang, Connie J; Judge, Daniel P et al. (2014) A Pkd1-Fbn1 genetic interaction implicates TGF-* signaling in the pathogenesis of vascular complications in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 25:81-91
Gerber, Elizabeth E; Gallo, Elena M; Fontana, Stefani C et al. (2013) Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma. Nature 503:126-30
Sengle, Gerhard; Tufa, Sara F; Sakai, Lynn Y et al. (2013) A correlative method for imaging identical regions of samples by micro-CT, light microscopy, and electron microscopy: imaging adipose tissue in a model system. J Histochem Cytochem 61:263-71
Robertson, Ian B; Rifkin, Daniel B (2013) Unchaining the beast; insights from structural and evolutionary studies on TGF* secretion, sequestration, and activation. Cytokine Growth Factor Rev 24:355-72
Sengle, Gerhard; Tsutsui, Ko; Keene, Douglas R et al. (2012) Microenvironmental regulation by fibrillin-1. PLoS Genet 8:e1002425
Todorovic, Vesna; Rifkin, Daniel B (2012) LTBPs, more than just an escort service. J Cell Biochem 113:410-8
Mariko, Boubacar; Pezet, Mylene; Escoubet, Brigitte et al. (2011) Fibrillin-1 genetic deficiency leads to pathological ageing of arteries in mice. J Pathol 224:33-44
Todorovic, Vesna; Finnegan, Erin; Freyer, Laina et al. (2011) Long form of latent TGF-? binding protein 1 (Ltbp1L) regulates cardiac valve development. Dev Dyn 240:176-87

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