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.
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.
|Walji, Tezin A; Turecamo, Sarah E; DeMarsilis, Antea J et al. (2016) Characterization of metabolic health in mouse models of fibrillin-1 perturbation. Matrix Biol 55:63-76|
|Bellini, C; Korneva, A; Zilberberg, L et al. (2016) Differential ascending and descending aortic mechanics parallel aneurysmal propensity in a mouse model of Marfan syndrome. J Biomech 49:2383-9|
|Smaldone, Silvia; Ramirez, Francesco (2016) Fibrillin microfibrils in bone physiology. Matrix Biol 52-54:191-7|
|Horiguchi, Masahito; Todorovic, Vesna; Hadjiolova, Krassimira et al. (2015) Abrogation of both short and long forms of latent transforming growth factor-Î² binding protein-1 causes defective cardiovascular development and is perinatally lethal. Matrix Biol 43:61-70|
|Dabovic, Branka; Robertson, Ian B; Zilberberg, Lior et al. (2015) Function of latent TGFÎ² binding protein 4 and fibulin 5 in elastogenesis and lung development. J Cell Physiol 230:226-36|
|Cook, J R; Carta, L; Galatioto, J et al. (2015) Cardiovascular manifestations in Marfan syndrome and related diseases; multiple genes causing similar phenotypes. Clin Genet 87:11-20|
|Cook, Jason R; Clayton, Nicholas P; Carta, Luca et al. (2015) Dimorphic effects of transforming growth factor-Î² signaling during aortic aneurysm progression in mice suggest a combinatorial therapy for Marfan syndrome. Arterioscler Thromb Vasc Biol 35:911-7|
|Sengle, Gerhard; Sakai, Lynn Y (2015) The fibrillin microfibril scaffold: A niche for growth factors and mechanosensation? Matrix Biol 47:3-12|
|Doyle, Jefferson J; Doyle, Alexander J; Wilson, Nicole K et al. (2015) A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome. Elife 4:|
|Robertson, Ian B; Horiguchi, Masahito; Zilberberg, Lior et al. (2015) Latent TGF-Î²-binding proteins. Matrix Biol 47:44-53|
Showing the most recent 10 out of 74 publications