Regulation of Cellular Phenotype Change in Thoracic Aortic Aneurysms

描述（由申请人提供）：

DESCRIPTION (provided by applicant): Thoracic aortic aneurysms (TAAs) develop as a consequence to abnormal remodeling of the aortic extracellular matrix (ECM). TAA development is influenced by a series of interrelated mechanisms that disrupt ECM homeostasis through the stimulation of proteolytic pathways, such as the matrix metalloproteinases (MMPs) and dysregulation of the production and deposition of ECM proteins. Importantly, these mechanisms are mediated in part through changes in the resident cellular constituents within the aortic wall. Numerous studies have demonstrated that aortic dilatation is accompanied by the apoptotic loss of smooth muscle cells, suggesting that the aortic fibroblast may be the key cellular mediator of ECM remodeling during aneurysm formation. Moreover, recent evidence from this laboratory suggests that aortic fibroblasts undergo a stable transformation to a myofibroblast phenotype, that is characterized by increased myosin staining (DDR2/Myh11) and enhanced production of both MMPs and ECM proteins. It is hypothesized that the transdifferentiation of fibroblasts is essential for TAA progression. However, the mediator(s) regulating this fibroblast-to-myofibroblast transition during TAA development remain undefined. One upstream signaling protein capable of regulating the structure and composition of the aortic ECM, and known to play an important role in mediating the fibroblast-to- myofibroblast transformation, is transforming growth factor-beta (TGF-?). TGF-? is a soluble peptide growth factor, produced by multiple cell types within the aortic wall, and is known to play a significant role in aortic root dilatation secondary to Marfan syndrome, but its involvement remains undefined in non-MFS etiologies of TAA. TGF-? is sequestered within the ECM, bound by latent TGF-? binding proteins. These latent complexes are proteolytic targets for key MMPs (MT1-MMP) that are induced during TAA development. Accordingly, using an established mouse model of TAA, and isolated primary aortic fibroblast cultures (normal and TAA), the role of fibroblast transdifferentiation in TAA development will be examined with the central hypothesis that MT1-MMP- dependent TGF-? signaling is essential for TAA development through the modulation of aortic fibroblast phenotype change. This hypothesis will be tested by demonstrating that selective targeting of fibroblast transdifferentiation can modulate TAA formation and progression, that increased TGF-? signaling during TAA development is a direct result of altered MT1-MMP-dependent release of TGF-? from latent ECM bound stores, and that indirect pharmacological inhibition of TGF-? signaling results in the attenuation of TAA development. The outcomes from this unified set of aims will establish a cause-effect relationship between MT1-MMP activation, TGF-? dependent myofibroblast differentiation, and TAA development.