In the adult heart, cardiovascular disease is often accompanied by extensive changes in the extracellular matrix (ECM) and reinitiation of genes expressed in early cardiac development. For example, mutations in the ECM gene fibrillin-1 result in an increase in TGFβ signaling that leads to aortic dissection and myxomatous valve degeneration in patients with Marfan's syndrome. Changes in the ECM are also initiated by matrix metalloproteinases that profoundly alter the matrix architecture by cleaving substrates including proteoglycans and collagens. How ECM proteolysis affects cell behavior and alters cell signaling is not well understood. Nevertheless, recent studies suggest that the appropriate balance between remodeling enzymes and their ECM substrates is critical for regulating cardiac development and maintaining homeostasis in the cardiovascular ECM. These studies are the first to explore the role of ADAMTS9, a member of the 'A Disintegrin and Metalloproteinase with ThromboSpondin motifs (ADAMTS) proteinase family, in the cardiovascular ECM. Homozygous gene-targeted mice have been generated for many of the matrix metalloproteinases of both the MMP (Matrix metalloproteinase) and ADAMTS families; ADAMTS9 is the only matrix proteinase that when both alleles are deleted from the genome causes embryological death (7.5 dpc) and heterozygousity results in an adult cardiac phenotype. In addition, the major substrate of ADAMTS9, versican, is essential for cardiac development. Published findings by the PI have determined that over-expression of versican variants that approximate different cleavage forms of versican have opposing effects on myocardial cell-cell attachment. These studies also demonstrated that versican cleavage is associated with key morphogenetic processes in cardiac outflow tract development. Our unpublished findings show that Adamts9+/LacZ heterozygous mice develop structural analogs of disease in the valves and aortic wall. We hypothesize that proteolytic cleavage of versican by ADAMTS9 is critical for the maintenance of the cardiovascular ECM in valvular and arterial tissue. Experiments: 1) Determine the phenotypic and signaling changes in vascular smooth muscle cells due to altered versican processing by ADAMTS9. 2) Determine the affect of abrogated versican processing on gene expression and cell behavior in the valves of Adamts9+/LacZ mice. 3) Examine versican processing and ADAMTS expression in human normal and diseased valves.
|Program type||Scientist Development Grant|
|Effective start/end date||01/01/2010 → 12/31/2013|