The endothelial cells (EC) lining the blood vessels are probably involved in the etiology of all vascular disease. The fluid mechanical forces resulting from blood flow and pressure may injure the EC, but this is as yet unproven. Tissue cultured EC provide a tool to prove (or disprove) this hypothesis, by subjecting the cells to physical forces in a controlled environment. Recent studies indicate that shear stress has dramatic effects on EC structure and function. Such in vitro studies bring two problems to the forefront. First, what is the best way to simulate the mechanical forces the ED experience in vivo? Second, if mechanical stress damages EC, what constitutes """"""""damage"""""""", short of outright detachment? We are uniquely qualified to answer these important questions. Our present system for subjecting EC to flow is capable of 1) a wide range of steady or pulsatile shear stresses (1-150 dynes/square cm), fluid dynamically well characterized, 2) continuous light microscopic videorecording, and 3) small """"""""medium-to-cell"""""""" ratio so that cell secretions can be measured, 4) long term (5 da.) experiments. Functional and structural assays for describing EC response in this system will be prostacyclin synthesis, angiotensin converting enzyme activity, macromolecular transport changes, extracellular matrix changes, cytoskeletal changes and morphometric analysis. The effects of steady and pulsatile shear stress, cyclic substrate deformation, and substrate permeability on EC will be assessed independently. Then these factors and forces will be combined into one device which most accurately simulates the blood/vessel wall interface. With this device, interaction between polymorphonuclear leukocytes and EC will be studied as a model of the inflammatory response. Interactions between platelets and EC will be studied as a model of thrombosis. Vascular graft endothelialization will be modelled with EC interactions with fibrin and biomaterials, with particular attention to explaining the lack of endothelialization observed in man. Finally, whether vessel location in the cardiovascular system or species or origin of the vessel affect EC response to physical forces will be determined.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL023016-08
Application #
3337122
Study Section
(SSS)
Project Start
1979-05-01
Project End
1987-04-30
Budget Start
1986-05-01
Budget End
1987-04-30
Support Year
8
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
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Schilling, W P; Mo, M; Eskin, S G (1992) Effect of shear stress on cytosolic Ca2+ of calf pulmonary artery endothelial cells. Exp Cell Res 198:31-5
Carosi, J A; Eskin, S G; McIntire, L V (1992) Cyclical strain effects on production of vasoactive materials in cultured endothelial cells. J Cell Physiol 151:29-36
Mueller, H W; Nollert, M U; Eskin, S G (1991) Synthesis of 1-acyl-2-[3H]acetyl-SN-glycero-3-phosphocholine, a structural analog of platelet activating factor, by vascular endothelial cells. Biochem Biophys Res Commun 176:1557-64
Sharefkin, J B; Diamond, S L; Eskin, S G et al. (1991) Fluid flow decreases preproendothelin mRNA levels and suppresses endothelin-1 peptide release in cultured human endothelial cells. J Vasc Surg 14:1-9
Mo, M; Eskin, S G; Schilling, W P (1991) Flow-induced changes in Ca2+ signaling of vascular endothelial cells: effect of shear stress and ATP. Am J Physiol 260:H1698-707
Diamond, S L; Sharefkin, J B; Dieffenbach, C et al. (1990) Tissue plasminogen activator messenger RNA levels increase in cultured human endothelial cells exposed to laminar shear stress. J Cell Physiol 143:364-71
Elliott, S J; Eskin, S G; Schilling, W P (1989) Effect of t-butyl-hydroperoxide on bradykinin-stimulated changes in cytosolic calcium in vascular endothelial cells. J Biol Chem 264:3806-10
Diamond, S L; Eskin, S G; McIntire, L V (1989) Fluid flow stimulates tissue plasminogen activator secretion by cultured human endothelial cells. Science 243:1483-5
Schilling, W P; Ritchie, A K; Navarro, L T et al. (1988) Bradykinin-stimulated calcium influx in cultured bovine aortic endothelial cells. Am J Physiol 255:H219-27

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