Endocytosis, the capture and internalization of extracellular macromolecules in vesicles derived from invagination of the cell surface, occurs in all mammalian cells. The intracellular fate of the endocytosed substances appears mainly to be degradation in the lysosomal system of the cell. In some cases however, a large proportion of vesicles do not fuse with lysosomes but pass out of the cell by reverse endocytosis. This occurs in the arterial endothelium which therefore functions as a dynamic barrier to the passage of macromolecules from the blood into the artery wall. Thus transendothelial flux of macromolecules such as lipoproteins is regulated by endocytosis. Focal proliferation of arterial smooth muscle cells (SMC) and lipoprotein-lipid accumulation is a characteristic feature of atherogenesis. Therefore, the control of endocytosis assumes importance in transendothelial transport of lipoproteins and their subsequent internalization in SMC. Little is known concerning normal control of endocytosis. Because atherogenesis is associated with altered growth properties of endothelium and SMC, the project is designed to investigate the relationships between growth and quantitative lipoprotein endocytosis in cultured vascular endothelium and SMC. The rates of endocytosis of low density lopoproteins (LDL) via several pathways will be measured in quiescent and growing vascular cells. Growth status will be manipulated in part by specific growth factors. The studies will be extended to include investigations of the effects of LDL charge upon selective entry and degradation in vescular cells. Quantitative data on control of endocytosis will be related to various postulated mechanisms of atherogenesis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Brigham and Women's Hospital
United States
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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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