Vessel Structure & Pressure:Transport and Atherogenesis

动脉粥样硬化是一种大动脉的疾病，开始于脂蛋白在动脉壁上的积聚，并发展为病变。这种积聚与较高的血浆脂蛋白浓度有关，因此脂蛋白在动脉壁内的转运和积聚一直是研究的重点。如果脂蛋白在血管壁上的运输和积累是动脉粥样硬化的关键，那么对这些过程的良好理解应该解释为什么不同的血管对疾病有不同的易感性，以及为什么这些易感性随着跨壁压力等条件的不同而不同。特别是，肺动脉(PA)和大静脉，如下腔静脉和大静脉，暴露在比大动脉低得多的跨壁压力下，通常对动脉粥样硬化具有抵抗力。但是，当暴露在动脉压力下时，PA在肺动脉高压和大静脉的情况下更容易患病。我们已经开发了一种内皮细胞水平的方法来运输和积聚到主动脉壁中，这似乎具有血管依赖性的特征。这项建议将这一方法扩展到一个更一般的场所，以详细了解跨壁压力、血管超微结构和内皮细胞周转如何影响低压PA和大静脉(下腔静脉)的运输和聚集。它不治疗血管重塑。该理论旨在模拟血管结构和压力条件在与动脉粥样硬化相关的脂蛋白运输过程中的作用。这项拟议的研究是通过动物实验和理论建模相结合的方式设计的，相互指导，以了解这些角色。特别是，该理论应该能够解释汤普金斯十年来的示踪剂浓度随深度进入血管壁的曲线，而与血管组织学不太一致的粗略理论无法解释。它还测试了这样一种假设，即脂质与动脉细胞外内膜基质结合并在那里聚集的动力学是不依赖于血管的；血管依赖性完全源于血管向组织提供游离低密度脂蛋白及其蛋白多糖类型/数量的特殊运输问题。长期目标是能够根据血管的超微结构和条件(例如跨壁压力)预测血管的脂肪堆积模式。假设这将与动脉粥样硬化的易感性相关，如果是这样的话，可以帮助理解血压对某些血管中动脉粥样硬化形成的影响。这项拟议研究的最终目标是提供预防和治疗人类动脉粥样硬化所需的信息。

Atherosclerosis is a disorder of the large arteries that begins with the accumulation of lipoproteins in the artery wall and develops into lesions. This accumulation is associated with high plasma lipoprotein concentrations, and thus lipoprotein transport into and accumulation in the artery wall has been the focus of intense study. If lipoprotein transport and accumulation in the vessel wall is the key to atherosclerosis, then a good understanding of these processes should explain why different vessels have different susceptibilities to disease and why these susceptibilities vary with conditions such as transmural pressure. In particular, the pulmonary artery (PA) and the large veins such as the inferior vena cava and the saphenous vein are exposed to much lower transmural pressures than the large arteries and are normally resistant to atherosclerosis. But, the PA becomes disease prone under pulmonary hypertension and large veins when exposed to artery pressure. We have developed an endothelial cell-level approach to the transport into and accumulation in the aortic wall, which seem to have vessel-in-dependent features. This proposal extends that approach to a more general venue for a detailed understanding of how the transmural pressure, vessel ultrastructure and endothelial cell turnover influence transport and accumulation in the low-pressure PA and the large vein (inferior vena cava). It does not treat vessel remodeling. The theory aims to model the roles of vessel structure and pressure conditions on the transport processes of lipoproteins in relation to atherosclerosis. The proposed research is designed by combining animal experimentation and theoretical modeling, each guiding the other, to understand these roles. In particular, the theory should be able to explain Tompkins' decade-old profiles of the tracer concentration-vs-depth into the vessel wall that coarser theories less in tune with the vessel's histology could not. It also tests the hypothesis that the kinetics of lipid binding to arterial extra-cellular intimal matrix and accumulation there is vessel independent; vessel dependence would derive solely from the vessel's peculiar transport problem that supplies free LDL to the tissue and its proteoglycan type/amount. The long-term goal is to be able to predict a vessel's lipid accumulation patterns based on its ultrastructure and conditions, e.g., transmural pressure. The hypothesis is that this will correlate with susceptibility to atherosclerosis and, if so, can contribute to an understanding of the effect of blood pressure on atherogenesis in certain vessels. The ultimate goal of the proposed research is to provide information needed for the prevention and treatment of atherosclerosis in humans.