Remodeling of the cellular and extracellular matrix components of the vascular wall is a critical event in the etiology of pulmonary vascular disease. A central player in this process is the medial smooth muscle cell. Past studies from this investigator have demonstrated an extensive phenotypic heterogeneity within the smooth muscle cells of both normal and diseased pulmonary vessels. In order to understand the origins of smooth muscle cell diversity, it is necessary to understand how the pulmonary vasculature develops. The elastic fiber network within the vessel wall contributes the elastic properties of both systemic and pulmonary vessels. For many years, elastic fibers were thought to exclusively serve a mechanical role in the extracellular matrix. It is now clear, however, that elastic fiber proteins act as important signaling molecules that interact with cell-surface receptors and bind and store growth factors. In this application, the primary investigator will investigate the hypothesis that tropoelastin and its associated microfibrillar proteins play an important role in smooth muscle cell maturation by providing informational and positional signals that influence smooth muscle cell differentiation and matrix production. He will also determine how abnormalities in this process influence functional properties of the pulmonary and systemic circulation. The first three specific aims will follow elastic fiber expression in the developing pulmonary circulation in vivo and in vitro.
The first aim has two parts: 1) To further define the pattern of elastic fiber protein (tropoelastin, fibrillin-1, fibrillin-2, MAGP, and LTBP-2) expression in the vessels of the developing lung. 2) To correlate elastic fiber expression with differentiation of vascular wall cells. Studies will also determine whether the onset of elastic expression in early vascular development is coordinated with expression of the TIE/angiopoietin signaling pathway. In the second and third aims studies will investigate whether elastin and other elastic fiber proteins influence the differentiation or recruitment of mesenchymal cells to the smooth muscle phenotype, and/or influence the spatial organization of SMC around endothelial cells in the developing vessel wall. The final specific aim will determine how altered expression of elastic fiber proteins contributes to changes in compliance of pulmonary vessels in knockout transgenic mice.
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| Broekelmann, Thomas J; Kozel, Beth A; Ishibashi, Hideaki et al. (2005) Tropoelastin interacts with cell-surface glycosaminoglycans via its COOH-terminal domain. J Biol Chem 280:40939-47 |
| Kelleher, Cassandra M; McLean, Sean E; Mecham, Robert P (2004) Vascular extracellular matrix and aortic development. Curr Top Dev Biol 62:153-88 |
| Kozel, Beth A; Ciliberto, Christopher H; Mecham, Robert P (2004) Deposition of tropoelastin into the extracellular matrix requires a competent elastic fiber scaffold but not live cells. Matrix Biol 23:23-34 |
| Werneck, Claudio C; Trask, Barbara Crippes; Broekelmann, Thomas J et al. (2004) Identification of a major microfibril-associated glycoprotein-1-binding domain in fibrillin-2. J Biol Chem 279:23045-51 |
| Faury, Gilles; Pezet, Mylene; Knutsen, Russell H et al. (2003) Developmental adaptation of the mouse cardiovascular system to elastin haploinsufficiency. J Clin Invest 112:1419-28 |
| Kozel, Beth A; Wachi, Hiroshi; Davis, Elaine C et al. (2003) Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. J Biol Chem 278:18491-8 |
| Ritty, Timothy M; Broekelmann, Thomas J; Werneck, Claudio C et al. (2003) Fibrillin-1 and -2 contain heparin-binding sites important for matrix deposition and that support cell attachment. Biochem J 375:425-32 |
| Davis, Elaine C; Roth, Robyn A; Heuser, John E et al. (2002) Ultrastructural properties of ciliary zonule microfibrils. J Struct Biol 139:65-75 |
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