The objective of the proposed research is to elucidate the role of rheological factors on transendothelial and intramural transport of macromolecules through the arterial wall. This interdisciplinary project represents a coordinated program of theoretical and experimental investigations. The proposed theoretical work involves the development of new models, based upon preliminary studies, to elucidate the mechanisms by which rheological factors affect the following transport processes: (a) attachment, detachment and deformation of plasmalemmal vesicles (variational principle and strain energy function), (b) transport of vesicles in the endothelium (continuum theory and Stokes flow), and (c) diffusion of macromolecules in the arterial wall substance (two-phase diffusion model). Parallel experimental studies will be performed to critically test the validity of the theories and to provide data for the improvement of the models. These experiments will be performed on isolated segments of canine common carotid arteries and on laboratory model systems. Emphasis will be placed on the effect of oscillatory rheological tests (systematic variations in stretch, pressure and flow) on the transport of macromolecules of different physiochemical properties (125I-albumin, 131I-fibrinogen, 3H-dextrans, 125I-lipoproteins, hemeundecapeptide, etc.) across the arterial wall. The transport processes will be determined by radioactivity assays and ultrastructural examinations. The results of these coordinated theoretical and experimental investigations on macromolecular transport should improve our understanding of the pathogenesis of incipient atheroma and the development of atherosclerosis.