The overall goal of this project is to determine the pathogenesis of adventitial remodeling after vascular injury. This process will be studied in a porcine model of coronary injury in order to examine acute and chronic remodeling changes. The impact of morphologic changes in the adventitia on luminal dimensions will be assessed using intravascular ultrasound in vivo. Cellular composition, cell proliferation, extracellular matrix components (collagens, elastin, fibronectin and proteoglycans) as well as matrix degrading enzymes will be determined in adventitial lesions. The applicant hypothesizes that adventitial myofibroblasts play a pivotal role in adventitial remodeling and proposes to demonstrate enhanced migration associated with increased matrix degrading activities followed by their enhanced synthetic function. To further elucidate the mechanism of adventitial remodeling, studies examining the role of TGF-b1 will be undertaken. TGF-b1 expression in the adventitia of remodeled vessels as well as the relationship between TGF-b1 expression and cell proliferation/matrix protein synthesis in the adventitia will be assessed. To determine the functional role of TGF-b1, two strategies designed to modulate the development of """"""""neoadventitia"""""""" will be employed. Thus, TGF-b1 gene transfer or antisense directed against TGF-b1 will be applied to the adventitia of porcine arteries in vivo to augment or inhibit adventitial lesions, respectively. The effects of overexpression or downregulation of TGF-b1 on adventitial remodeling, cell proliferation and extracellular matrix accumulation in the adventitia will be determined. The long-term objective of this study is to define the mechanisms underlying vascular remodeling taking place in a wide spectrum of cardiovascular disorders.
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