Atherosclerosis: Cytomegalovirus, Shear Stress, and Endothelial Cells

描述(申请人提供)：这项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。动脉粥样硬化主要发生在动脉树上有分支和弯曲的区域，这些区域的血液流动受到干扰，切应力低且不均匀。越来越多的证据表明，具有高切应力的层流血流可以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，并且扰动的血流上调了促动脉粥样硬化、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，巨细胞病毒在动脉粥样硬化形成中的作用机制是什么？许多研究表明，人巨细胞病毒感染可诱导内皮细胞表达致动脉粥样硬化基因，但这些研究都是在没有流动或剪应力的静态细胞培养中进行的。同样，不同的血流模式对内皮细胞功能的作用从未在HCMV感染的背景下进行过研究。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(大血管和微血管)进行HCMV感染和切应力研究，使得数据的比较非常困难。我们假设血流条件会影响HCMV与主动脉内皮细胞的特异性相互作用，进而调节内皮细胞的功能。这一建议的新颖之处在于，它通过多方面的方法解决了人巨细胞病毒感染和血流动力学在动脉粥样硬化形成中的作用。主要目的是确定高剪应力和低剪应力下人巨细胞病毒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)剪应力如何影响内皮细胞中人巨细胞病毒感染的进展？2)在不同的血流模式和切应力下，人巨细胞病毒如何影响动脉内皮细胞致动脉粥样硬化和血栓前基因的表达？这项建议的目的是为动脉粥样硬化的发病机制提供新的见解。实现这一目标将有助于制定旨在预防和治疗动脉粥样硬化性疾病的新战略。

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.