The long-term objectives of this research are to define the roles of arterial mass transport and structural features that cause the accumulation of atherogenic substances in the lining of arteries to produce arteriosclerosis. To achieve the necessary experimental control for such studies, an in vitro arterial organ support system (OSS) was developed. The following measurements will be made on metabolically-supported arteries in this system: 1) The arterial uptake (M mg cm-2), and transmural concentration distributions [c(x) mg cm-3], of radiolabeled albumin, LDL, oxidized DL, and HDL will be determined under controlled conditions of pressure, stretch, composition of local bathing milieu, intimal thickening, etc. 2) The intimal surface concentrations of the above proteins will be measured to determine intimal sieving of these molecules. 3) The c(x) contours of these proteins will be correlated with the associated structural and cellular elements in the tissue by light and electron microscopy. 4) Mathematical modeling of c(x) contours in relation to structure will be developed for data analysis. 5) The physiological state of the tissues will be monitored by routine chemistries, e.g., glucose, lactate, etc., and in some cases by special measurements, e.g., tissue ATP/ADP, etc. The above methods will be used to study the following unsolved problems relevant to atherogenesis: A) effect on endothelial permeability of various incubation media such as blood, serum, etc.; B) isolation and study of a new serum actor that bolsters the endothelial barrier; C) effect of growth factors on endothelial permeability; D) effect of LDL, oxidized LDL, HDL, and linoleic acid on arterial permeability; E) effect of agents from cigarette smoke on endothelial permeability; F) effect of HDL on the transmural transport of LDL and oxidized LDL; G) effect of pulsatile pressure on transendothelial transport; H) effect of positive and negative pressures on transmural transport; 1) effect of vessel wall strain on transport and (tissue) binding of lipoproteins; J) transport and structure at an arterial site shown to be vulnerable to development of arteriosclerosis; K) endothelial permeability changes associated with selective removal of structural matrix substances; L) comparative study of albumin, LDL, and oxidized LDL transport in arteries with injury-induced intimal thickening; and M) effect of mural thrombus on transport and intimal accumulation of albumin, LDL, and oxidized DL.
These specific aims address gaps in our understanding of how atherogenic substances accumulate in the linings of arteries to cause arteriosclerosis, heart attacks, and strokes.
Showing the most recent 10 out of 12 publications
