Atherosclerosis, the underlying cause of most human heart disease, results from a focal imbalance of the normal equilibria of the arterial wall. While metabolic cooperation between vascular cells is essential for the maintenance of normal vascular homeostasis, little is known about the nature of these interactions or whether disturbance of their equilibria will precipitate irreversible pathological changes in arterial tissue. We propose to investigate mechanisms of cellular interactions between vascular endothelium, smooth muscle cells (SMC) and monocyte-derived macrophages in vitro and in intact vascular tissue. Two separate general mechanisms of cell cooperativity will be studied: a) cell contact-mediated communication via gap junctional channels connecting the cytoplasm of adjacent cells, and b) humoral communication in which diffusible substances secreted by one cell type pass via the interstitial fluid to specific receptors on the surface of the other cell population. The effects of cell biological pertubations associated with hypercholesterolemia (cellular cholesterol, lipoprotein metabolism), a major risk factor for atherogenesis, will be investigated. New techniques to probe cellular communication in intact normal and atherosclerotic (fibrofatty lesion) vascular tissue will be tested and developed to integrate the in vitro findings with vessel wall biology and pathology. Gap junctional-mediated cell interactions will be investigated biochemically in vitro (transfer of 3H-nucleotides, fluorescent dyes and putative second messengers such as cyclic nucleotides and Ca++ and electrophysiological measurements) using cocultures of endothelial cells, SMC and macrophages. The effects of various mediators of gap junctional transfer, particularly cellular cholesterol composition, will be evaluated. The effects of heterocellular communication upon receptor-mediated lipoprotein metabolism in endothelial cells will be measured. Gap junctional communication will also be investigated in normal and atherosclerotic intact arterial tissues both at the ultrastructural level and functionally using new methods to deliver tracers to the vascular tissue. The regulation of platelet-derived growth factor-like mitogens (c-sis related) synthesized and secreted by endothelial cells will be investigated in the context of the interactions of these cells with SMC and macrophages using molecular biology techniques.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL036049-06
Application #
3350599
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1988-08-01
Project End
1992-07-31
Budget Start
1990-08-01
Budget End
1991-07-31
Support Year
6
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Davies, Peter F; Civelek, Mete (2011) Endoplasmic reticulum stress, redox, and a proinflammatory environment in athero-susceptible endothelium in vivo at sites of complex hemodynamic shear stress. Antioxid Redox Signal 15:1427-32
Davies, Peter F; Civelek, Mete; Fang, Yun et al. (2010) Endothelial heterogeneity associated with regional athero-susceptibility and adaptation to disturbed blood flow in vivo. Semin Thromb Hemost 36:265-75
Davies, Peter Francis (2008) Endothelial transcriptome profiles in vivo in complex arterial flow fields. Ann Biomed Eng 36:563-70
Simmons, Craig A; Grant, Gregory R; Manduchi, Elisabetta et al. (2005) Spatial heterogeneity of endothelial phenotypes correlates with side-specific vulnerability to calcification in normal porcine aortic valves. Circ Res 96:792-9
Passerini, Anthony G; Shi, Congzhu; Francesco, Nadeene M et al. (2005) Regional determinants of arterial endothelial phenotype dominate the impact of gender or short-term exposure to a high-fat diet. Biochem Biophys Res Commun 332:142-8
Magid, Richard; Davies, Peter F (2005) Endothelial protein kinase C isoform identity and differential activity of PKCzeta in an athero-susceptible region of porcine aorta. Circ Res 97:443-9
Davies, Peter F; Passerini, Anthony G; Simmons, Craig A (2004) Aortic valve: turning over a new leaf(let) in endothelial phenotypic heterogeneity. Arterioscler Thromb Vasc Biol 24:1331-3
Davies, Peter F (2004) Molecular phenotypes of atherosclerosis: fingering the perpetrators. Arterioscler Thromb Vasc Biol 24:1746-7
Simmons, Craig A; Zilberberg, Jenny; Davies, Peter F (2004) A rapid, reliable method to isolate high quality endothelial RNA from small spatially-defined locations. Ann Biomed Eng 32:1453-9
Davies, Peter F; Zilberberg, Jenny; Helmke, Brian P (2003) Spatial microstimuli in endothelial mechanosignaling. Circ Res 92:359-70

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