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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL029095-12
Application #
3340285
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1985-09-01
Project End
1995-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
12
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Ohio State University
Department
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Fry, Donald L (2002) Arterial intimal-medial permeability and coevolving structural responses to defined shear-stress exposures. Am J Physiol Heart Circ Physiol 283:H2341-55
Henderson, J M; Aukerman, J A; Clingan, P A et al. (1999) Effect of alterations in femoral artery flow on abdominal vessel hemodynamics in swine. Biorheology 36:257-66
Fry, D L; Herderick, E E; Johnson, D K (1993) Local intimal-medial uptakes of 125I-albumin, 125I-LDL, and parenteral Evans blue dye protein complex along the aortas of normocholesterolemic minipigs as predictors of subsequent hypercholesterolemic atherogenesis. Arterioscler Thromb 13:1193-204
Friedman, M H; Fry, D L (1993) Arterial permeability dynamics and vascular disease. Atherosclerosis 104:189-94
Fry, D L; Haupt, M W; Pap, J M (1992) Effect of endothelial integrity, transmural pressure, and time on the intimal-medial uptake of serum 125I-albumin and 125I-LDL in an in vitro porcine arterial organ-support system. Arterioscler Thromb 12:1313-28
Fry, D L; Pap, J M (1992) Effect of various blood-derived and semisynthetic nutrient media on in vitro uptake of 125I-albumin across the intact porcine aortic endothelial surface in an organ-support system. Arterioscler Thromb 12:357-68
Pap, J M; Hammer, D F; Fry, D L et al. (1990) Nucleotide profiles in normal minipig arterial tissue. Arteriosclerosis 10:745-50
Pap, J M (1990) Long-term follow-up of catheter-induced intimal injury from routine coronary angiography in moderately hypercholesterolemic minipigs. Cathet Cardiovasc Diagn 20:139-49
Fry, D L (1987) Mass transport, atherogenesis, and risk. Arteriosclerosis 7:88-100
Pap, J M (1987) Catheter-induced intimal injury during routine coronary catheterization in dogs. Cathet Cardiovasc Diagn 13:57-73

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