Atherosclerosis: Cytomegalovirus, Shear Stress, and Endothelial Cells

描述（由申请人提供）：该提案的重要性在于它关注心血管疾病，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具有分支和弯曲的动脉树区域，其中血流受到干扰，剪切应力低且不均匀。有越来越多的证据表明，层流高切应力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，和干扰流上调促动脉粥样硬化，促炎和促凝血基因。长期以来，人们一直怀疑人巨细胞病毒（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在动脉粥样硬化形成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的致动脉粥样硬化基因表达，但这些研究都是在静态细胞培养中进行的，其中没有流动或剪切应力。同样，在HCMV感染的背景下，从未研究过不同血流模式对内皮细胞功能的作用。此外，使用来自不同解剖位置（脐静脉、脑、主动脉）的不同类型的内皮细胞（大血管与微血管）进行HCMV感染和剪切应力研究使得数据比较非常困难。我们假设血流条件影响HCMV与主动脉内皮细胞的特异性相互作用，进而调节内皮细胞功能。该提案的新奇在于，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形成中的作用。主要目的是确定HCMV和主动脉内皮细胞之间的双向相互作用在高和低剪切应力和回答以下问题：1）剪切应力如何影响HCMV感染的进展，在内皮细胞？以及2）在不同的流动模式和剪切应力下，HCMV如何影响主动脉内皮细胞中致动脉粥样硬化和血栓形成基因的表达？该建议的目的是提供新的见解动脉粥样硬化的发病机制。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.