The goal is to understand the effects of mechanical forces resulting from blood flow and vessel wall strain on the endothelial cells lining the cardiovascular system. State of the art Theological, cell, and molecular biology techniques will be used to study problems which impact directly on atherosclerosis, inflammation, and thrombosis. The overall hypothesis is that expression of atheroprotective versus atherogenic endothelial cell phenotypes depends on the balance of generation and removal of reactive oxygen species, which is strongly modulated by blood flow and wall strain. Endothelial cells will be subjected to steady shear stress, non- reversing pulsatile shear stress (atheroprotective - high mean wall shear stress), and reversing pulsatile shear stress (atherogenic - low mean wall shear stress). The effects of these 3 regimens on endothelial cell gene expression and functional sequelae will be examined in the first specific aim.
In specific aim 2, the functional contribution(s) of cytochromes P4501AT and 1B1, the genes most highly up-regulated under steady shear stress in previous microarray studies will be assessed. We hypothesize that these proteins produce lipid metabolites that are an endothelial-derived hyperpolarizing factor and a PPARgamma- activating ligand, either of which would be atheroprotective.
In specific aim 3, the functional contribution of connective tissue growth factor and cysteine-rich 61 genes, which were strongly down-regulated by shear stress, and their proteins, which have been found in atherosclerotic plaques, will be determined.
The final aim will focus on cyclic strain effects on reactive oxygen species signaling pathways. Vessel wall strain and fluid shear stress impose quite different mechanical loads on endothelial cells and can lead to different effects on gene expression (e.g.endothelin-1 and monocyte chemotactic protein-1). Some vascular regions prone to atherosclerosis have high wall strains, that may mitigate the atheroprotective effect of shear stress. Elucidating how cells in the vessel wall respond to changes in mechanical forces will lead to better strategies for prevention and treatment of cardiovascular diseases, a leading cause of death in the United States, claiming almost 2,600 Americans daily. For 2005, the estimated direct and indirect costs of cardiovascular diseases and stroke in the United States are $393.5 billion. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL018672-29A2
Application #
7212761
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Kindzelski, Andrei L
Project Start
1976-06-30
Project End
2011-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
29
Fiscal Year
2007
Total Cost
$373,500
Indirect Cost
Name
Georgia Institute of Technology
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30332
Sung, Derek C; Bowen, Caitlin J; Vaidya, Kiran A et al. (2016) Cadherin-11 Overexpression Induces Extracellular Matrix Remodeling and Calcification in Mature Aortic Valves. Arterioscler Thromb Vasc Biol 36:1627-37
Lee, Cho-Yin; Lou, Jizhong; Wen, Kuo-Kuang et al. (2016) Regulation of actin catch-slip bonds with a RhoA-formin module. Sci Rep 6:35058
Bowen, Caitlin J; Zhou, Jingjing; Sung, Derek C et al. (2015) Cadherin-11 coordinates cellular migration and extracellular matrix remodeling during aortic valve maturation. Dev Biol 407:145-57
Lee, Cho-yin; Lou, Jizhong; Wen, Kuo-kuang et al. (2013) Actin depolymerization under force is governed by lysine 113:glutamic acid 195-mediated catch-slip bonds. Proc Natl Acad Sci U S A 110:5022-7
Lee, Sungmun; Eskin, Suzanne G; Shah, Ankit K et al. (2012) Effect of zinc and nitric oxide on monocyte adhesion to endothelial cells under shear stress. Ann Biomed Eng 40:697-706
Coburn, L A; Damaraju, V S; Dozic, S et al. (2011) GPIbýý-vWF rolling under shear stress shows differences between type 2B and 2M von Willebrand disease. Biophys J 100:304-12
Conway, Daniel E; Lee, Sungmun; Eskin, Suzanne G et al. (2010) Endothelial metallothionein expression and intracellular free zinc levels are regulated by shear stress. Am J Physiol Cell Physiol 299:C1461-7
Conway, Daniel E; Williams, Marcie R; Eskin, Suzanne G et al. (2010) Endothelial cell responses to atheroprone flow are driven by two separate flow components: low time-average shear stress and fluid flow reversal. Am J Physiol Heart Circ Physiol 298:H367-74
Conway, Daniel E; Sakurai, Yumiko; Weiss, Daiana et al. (2009) Expression of CYP1A1 and CYP1B1 in human endothelial cells: regulation by fluid shear stress. Cardiovasc Res 81:669-77
Williams, Marcie R; Sakurai, Yumiko; Zughaier, Susu M et al. (2009) Transmigration across activated endothelium induces transcriptional changes, inhibits apoptosis, and decreases antimicrobial protein expression in human monocytes. J Leukoc Biol 86:1331-43

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