The significance of this proposal is that it focuses on cardiovascular diseases, a leading cause of mortality in industrialized nations. Atherosclerosis preferentially develops in regions of the arterial tree with branches and curvatures, where blood flow is disturbed and shear stress is low and non-uniform. There is increasing evidence that laminar blood flow with high shear stress modulates gene expression in endothelial cells to protect against atherosclerosis, inflammation and coagulation, and that disturbed flow upregulates proatherosclerotic, proinflammatory, and procoagulant genes. It has long been suspected that human cytomegalovirus (HCMV) infection is a risk factor for vascular disease such as atherosclerosis, arterial restenosis, and transplant vascular sclerosis. The key question is what is the mechanism underlying HCMV's role in atherogenesis? Many studies have shown that HCMV infection induces proatherogenic gene expression in endothelial cels, but these studies were all performed in static cell culture, where there is no flow or shear stress. Likewise, the role of differential blood flow patterns on endothelial cell function has never been studied in the context of HCMV infection. In addition, the use of different types of endothelial cells (macrovascular vs. microvascular) from different anatomic locations (umbilical vein, brain, aorta) both for HCMV infection and shear stress studies makes comparison of data very difficult. We hypothesize that flow conditions affect HCMV interaction specifically with aortic endothelial cells and that this in turn modulates endothelial cell function. The novelty of this proposal is that it addresses the roles of HCMV infection and flow dynamics in atherogenesis by a multifaceted approach. The major aim is to determine the bi-directional interactions between HCMV and aortic endothelial cells under high vs. low shear stress and answer the following questions: 1) How does shear stress affect the progression of HCMV infection in the endothelial cells? And 2) How does HCMV affect proatherogenic and prothrombotic gene expression in the aortic endothelial cells under different patterns of flow and shear stress? The objective of this proposal is to provide novel insights into the pathogenesis of atherosclerosis. Accomplishment of this goal will facilitate the development of new strategies designed to prevent and treat atherosclerotic disease.

Public Health Relevance

Atherosclerosis is the major cause of cardiovascular diseases, and its impact on health care costs is enormous. Hemodynamic factors are known to be major regulators of atherosclerosis, and human cytomegalovirus (HCMV) infection has been put forward as an important factor in disease progression. The proposed project employs novel approaches to study the effects of HCMV infection on endothelial cell functions under a dynamic flow environment, and the results will fill the current gap in our understanding of bi-directional interactions between the virus and vascular cells in physiological and pathophysiological flow environments, thus facilitating the discovery of new cost-effective interventions.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Virology - A Study Section (VIRA)
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Beisel, Christopher E
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University of California San Diego
Schools of Pharmacy
La Jolla
United States
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