The objective of the proposed research is to identify and relate the mechanisms, in vivo in suitable experimental models, which a) regulate the adaptation of arteries to changes in flow and pressure, b) determine the localization of plaques under conditions of hypercholesterolemia, and c) account for the interactions among hypercholesterolemia, plaque formation and the adaptive mechanisms to altered wall shear and tensile stresses. We have previously described a close relationship between wall shear stress and plaque localization, and developed an experimental model of lesion prone and lesion resistant regions. We have characterized the quantitative relationships among wall shear stress, tensile stress and artery wall infrastructure. These findings have revealed that artery wall adaptation to altered flow and pressure, plaque localization and the compensatory enlargement and modelling of arteries and plaques are a closely related phenomena. The proposed investigations will be carried out at the structural, cellular and molecular level, utilizing rabbit models designed to increase flow (arterio-venous fistula), decrease flow (carotid outflow ligation), alter pressure and establish lesion prone and lesion resistant regions (aortic coarctation). Our methods include ultrastructural, morphometric and chemical determinations of artery wall composition (elastin, collagen (Types I, III, IV and their respective proteases), and quantitation of cell proliferation and hypertrophy. Characterization of gene expression for these features, including in situ hybridization is expected to clarify both the sequence and spatial localization of the elicited changes in the absence and presence of hypercholesterolemia and plaque formation. An essential feature will be the correlation of spatial localization of our findings with the corresponding quantitative flow field characterizations in Project 0031 and the related biomechanical-cellular interactions revealed in Project 0034. Our research should provide new insights into the nature and limits of vessel wall adaptation to altered mechanical conditions and to the formation of plaques.