Vessel Structure & Pressure:Transport and Atherogenesis

动脉粥样硬化是大动脉的一种疾病，始于脂蛋白在动脉壁的积累，并发展成病变。这种积累与高血浆脂蛋白浓度有关，因此脂蛋白在动脉壁的转运和积累一直是研究的重点。如果脂蛋白在血管壁的运输和积聚是动脉粥样硬化的关键，那么对这些过程的良好理解应该可以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跨壁压力等条件而变化。特别是肺动脉（PA）和大静脉（如下腔静脉和隐静脉）的跨壁压力比大动脉低得多，通常对动脉粥样硬化有抵抗力。但肺动脉高压和大静脉下，肺动脉受压时，PA易发病。我们已经开发了一种内皮细胞水平的方法来运输和积聚在主动脉壁，这似乎具有血管依赖性的特征。该建议将该方法扩展到更一般的场所，以详细了解跨壁压力、血管超微结构和内皮细胞更新如何影响低压PA和大静脉（下腔静脉）的运输和积累。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。本研究通过动物实验和理论建模相结合，相互指导，来理解这些作用。特别是，该理论应该能够解释汤普金斯十年前对示踪剂浓度与血管壁深度的描述，这是不太符合血管组织学的粗糙理论无法解释的。它还验证了脂质与动脉细胞外内膜基质结合和积累的动力学与血管无关的假设；血管依赖性仅来源于血管特有的运输问题，即向组织提供游离LDL及其蛋白聚糖类型/数量。长期目标是能够根据其超微结构和条件（例如，跨壁压力）预测血管的脂质积累模式。假设这将与动脉粥样硬化的易感性相关，如果是这样，可以有助于理解血压对某些血管粥样硬化的影响。这项研究的最终目的是为预防和治疗人类动脉粥样硬化提供所需的信息。

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.