: Endothelial cell properties are affected by hemodynamics, various systemic chemicals and signals, and their attachment matrix. In an effort to extend current understanding of both atherogenesis and factors complicating successful treatment of occluded coronary arteries, this project will investigate the effects of hemodynamic forces, angiotensin I/II, and the cellular inflammatory response on endothelial cell physiology. Local synthesis of angiotensin II by endothelial membrane bound angiotensin converting enzyme (ACE) and the angiotensin type I receptor (AT1) may have potent effects on local endothelial dysfunction and the development of coronary artery disease. The inflammatory cytokine interleukin-l (IL-1) likely plays an important role in the alteration of endothelial phenotype observed in the presence of cellular stressors such as extremes of hydrodynamic pressure and angiotensin I/II. Many effects of IL-1 upon vascular endothelial cells are identical to those associated with angiotensin exposure and vascular activation by fluid forces. As such, work will be performed to elucidate the contributions of IL-1 to the effects of culture stimulation with pressure and angiotensin. Syndecans-l (present in the glycocalyx) and 4 (co-localized to focal adhesions) are common endothelial cell surface molecules that can be readily shed in response to cellular injury or stress and thereby promote monocyte adhesion. We hypothesize that modulation of two in vitro endothelial cell culture properties 1) hemodynamic pressure and 2) angiotensin I/II concentrations affects endothelial cell phenotype as related to 1) glycocalyx properties, 2) receptor/protein expression, and 3) attachment characteristics. Encompassed by this hypothesis are the mechanisms by which pressure and angiotensin I/II exert their effects. It is proposed that pressure and angiotensin I/II activate cell stress signaling pathways (i.e. mitogen activated protein kinase cascades and protein kinase C) that result in the shedding of specific glycocalyx components (e.g. syndecan proteoglycans) and the induction of proinflammatory physiological responses (e.g. interleukin-1 production, monocyte adhesion receptor production, monocyte chemoattractant protein-1production). It is further proposed that while pressure and angiotensin directly induce these events, the production of intlerleukin-1 significantly amplifies each of the physiological responses and becomes a controlling factor upon endothelial dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068916-04
Application #
6891563
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Lin, Michael
Project Start
2002-06-01
Project End
2005-07-31
Budget Start
2005-06-01
Budget End
2005-07-31
Support Year
4
Fiscal Year
2005
Total Cost
$13,570
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Shepherd, Robert D; Kos, Stephanie M; Rinker, Kristina D (2011) Flow-dependent Smad2 phosphorylation and TGIF nuclear localization in human aortic endothelial cells. Am J Physiol Heart Circ Physiol 301:H98-H107
Shepherd, Robert D; Kos, Stephanie M; Rinker, Kristina D (2009) Long term shear stress leads to increased phosphorylation of multiple MAPK species in cultured human aortic endothelial cells. Biorheology 46:529-38
Rinker, Kristina D; Kirkpatrick, Allison P; Ting-Beall, H Ping et al. (2004) Linoleic acid increases monocyte deformation and adhesion to endothelium. Atherosclerosis 177:275-85
Shepherd, Robert D; Rinker, Kristina D (2004) Bioluminescence-based ATP assays using a charge-coupled device imaging system. Biotechniques 37:208, 210