LOCAL INTIMAL-MEDIAL UPTAKES OF I-125 ALBUMIN, I-125 LDL, AND PARENTERAL EVANS BLUE-DYE PROTEIN COMPLEX ALONG THE AORTAS OF NORMOCHOLESTEROLEMIC MINIPIGS AS PREDICTORS OF SUBSEQUENT HYPERCHOLESTEROLEMIC ATHEROGENESIS

This report describes the normalized intimal-medial uptakes [uptake (M, mg . cm-2) divided-by serum concentration (c0, mg - cm-3)] of I-125-albumin, I-125-low-density lipoprotein (LDL), and in vivo Evans blue dye (EBD)-albumin complex as functions of pressure (P), time (t), molecular species (i), and location (z) along a ventral longitudinal z axis of the normal, intact, aortic endothelial surface in adult normocholesterolemic Sinclair Research Farm (SRF) minipigs and compares these uptake (M/c0) measurements with atherogenesis in hypercholesterolemic cohorts. Uptakes of porcine serum I-125-albumin (n=21) and I-125-LDL (n=10) were measured in freshly excised, metabolically supported aortas using a recently developed organ-support system. In vivo intimal-medial EBD uptake vs z data were measured photometrically on opened descending aortas from another group (n=6) of normocholesterolemic, adult, SRF minipigs 18 hours after the intravenous administration of EBD. For comparison purposes, the corresponding incidence of atherosclerotic lesions along the aortic z axis was calculated using topographic data from hypercholesterolemic minipig cohorts (n=39). The results showed that uptakes varied greatly with t, z, and macromolecule (i) but not with P. More specifically, the value of M/c0 at any location (z) rose with t, was insensitive to P, decreased with macromolecular (i) size, and varied with z in a pattern that ''peaked'' in the upstream region, decreased to a nadir in the downstream region, and then rose again as it approached the abdominal celiac orifice. The spatially z-averaged uptake rates for the three different labeled serum proteins were 0.31 x 10(-3) CM . h-1 for I-125-albumin, 0.42 x 10-3 cm . h-1 for EBD-albumin, and 0.04 x 10(-3) cm . h-1 for I-125-LDL. Nondimensionalized analysis of the individual sets of uptake data indicated that the overall uptake relationship [M(t,P,z,i)/c(io), cm] could be characterized empirically by the simple product of two separate functions: one, a ''scaling function'' [m(z,i)], that described the uptake magnitude for a given i and z and appeared to be independent of t or P; the other, a ''shape function'' [s(t,P)], that described the shapes of the uptake vs t and P relationships and appeared to be independent of z or i. The ''scaling function'' [m(z,i)] vs z contour appeared to correlate well with the corresponding atherosclerotic lesion incidence vs z contour from the group of hypercholesterolemic minipig cohorts. Assuming passive transport, it was shown (''Appendix'') that m (z,i) can be interpreted physically in terms of an endothelial diffusive permeability coefficient (P, cm . s-1). We conclude that (1) transport of albumin and LDL across the intact, normocholesterolemic, aortic endothelial surface is independent of pressure; (2) in vivo intimal-medial uptake of EBD can be used as a reasonable measure of I-125-albumin uptake; and (3) intimal-medial uptake rates of I-125-albumin, I-125-LDL, and in vivo EBD in the normocholesterolemic state correlate with the local probability of subsequent atherogenesis in the hypercholesterolemic state.