Atherosclerosis: Cytomegalovirus, Shear Stress, and Endothelial Cells

描述（由申请人提供）：本提案的意义在于，它侧重于心血管疾病，这是工业化国家死亡的主要原因。动脉粥样硬化优先发生在动脉树有分支和弯曲的区域，在那里血流受到干扰，剪切应力低且不均匀。越来越多的证据表明，高剪切应力下的层流血流调节内皮细胞的基因表达，以防止动脉粥样硬化、炎症和凝血，而血流紊乱会上调促动脉粥样硬化、促炎症和促凝基因。长期以来，人们一直怀疑人类巨细胞病毒（HCMV）感染是动脉粥样硬化、动脉再狭窄和移植血管硬化等血管疾病的危险因素。关键问题是HCMV在动脉粥样硬化中的作用机制是什么？许多研究表明，HCMV感染诱导内皮细胞中致动脉粥样硬化基因的表达，但这些研究都是在静态细胞培养中进行的，没有流动或剪切应力。同样，在HCMV感染的背景下，不同血流模式对内皮细胞功能的作用也从未被研究过。此外，HCMV感染和剪切应力研究使用不同解剖位置（脐静脉、脑、主动脉）的不同类型内皮细胞（大血管和微血管），使得数据比较非常困难。我们假设血流条件会影响HCMV与主动脉内皮细胞的相互作用，进而调节内皮细胞的功能。该建议的新颖之处在于，它通过多方面的方法解决了HCMV感染和血流动力学在动脉粥样硬化发生中的作用。主要目的是确定高、低剪切应力下HCMV与主动脉内皮细胞之间的双向相互作用，并回答以下问题：1)剪切应力如何影响内皮细胞中HCMV感染的进展？2) HCMV在不同血流和剪应力模式下如何影响主动脉内皮细胞中致动脉粥样硬化和血栓形成前基因的表达？这项提议的目的是为动脉粥样硬化的发病机制提供新的见解。这一目标的实现将促进旨在预防和治疗动脉粥样硬化疾病的新策略的发展。

DESCRIPTION (provided by applicant): 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.