School of Biological Sciences and Medical Engineering, Southeast University, Nanjing 210096, China.
School of Biological Sciences and Medical Engineering, Southeast University, Nanjing 210096, China; School of Chemistry, Physics and Mechanical Engineering, Queensland University of Technology, Brisbane, QLD 4001, Australia.
J Theor Biol. 2018 Aug 7;450:53-65. doi: 10.1016/j.jtbi.2018.04.031. Epub 2018 Apr 26.
Observational studies have identified angiogenesis from the adventitial vasa vasorum and intraplaque hemorrhage (IPH) as critical factors in atherosclerotic plaque progression and destabilization. Here we propose a mathematical model incorporating intraplaque neovascularization and hemodynamic calculation with plaque destabilization for the quantitative evaluation of the role of neoangiogenesis and IPH in the vulnerable atherosclerotic plaque formation. An angiogenic microvasculature is generated by two-dimensional nine-point discretization of endothelial cell proliferation and migration from the vasa vasorum. Three key cells (endothelial cells, smooth muscle cells and macrophages) and three key chemicals (vascular endothelial growth factors, extracellular matrix and matrix metalloproteinase) are involved in the plaque progression model, and described by the reaction-diffusion partial differential equations. The hemodynamic calculation of the microcirculation on the generated microvessel network is carried out by coupling the intravascular, interstitial and transvascular flow. The plasma concentration in the interstitial domain is defined as the description of IPH area according to the diffusion and convection with the interstitial fluid flow, as well as the extravascular movement across the leaky vessel wall. The simulation results demonstrate a series of pathophysiological phenomena during the vulnerable progression of an atherosclerotic plaque, including the expanding necrotic core, the exacerbated inflammation, the high microvessel density (MVD) region at the shoulder areas, the transvascular flow through the capillary wall and the IPH. The important role of IPH in the plaque destabilization is evidenced by simulations with varied model parameters. It is found that the IPH can significantly speed up the plaque vulnerability by increasing necrotic core and thinning fibrous cap. In addition, the decreased MVD and vessel permeability may slow down the process of plaque destabilization by reducing the IPH dramatically. We envision that the present model and its future advances can serve as a valuable theoretical platform for studying the dynamic changes in the microenvironment during the plaque destabilization.
观察性研究已经确定，源自血管外膜血管的血管生成和斑块内出血（IPH）是动脉粥样硬化斑块进展和不稳定的关键因素。在这里，我们提出了一个数学模型，该模型将斑块内新生血管形成和斑块不稳定的血流动力学计算相结合，用于定量评估新生血管形成和 IPH 在易损性动脉粥样硬化斑块形成中的作用。通过从血管外膜血管生成内皮细胞增殖和迁移的二维九点离散化生成血管生成微血管。三个关键细胞（内皮细胞、平滑肌细胞和巨噬细胞）和三个关键化学物质（血管内皮生长因子、细胞外基质和基质金属蛋白酶）参与斑块进展模型，并通过反应扩散偏微分方程进行描述。通过将血管内、间质和跨血管流动耦合，对生成的微血管网络上的微循环进行血流动力学计算。根据扩散和伴随间质液流动的对流，将间质域中的血浆浓度定义为 IPH 区域的描述，以及跨漏壁的血管外运动。模拟结果表明，在动脉粥样硬化斑块易损性进展过程中出现了一系列病理生理现象，包括不断扩大的坏死核心、炎症加剧、肩部区域的高微血管密度（MVD）区域、穿过毛细血管壁的跨血管流动和 IPH。通过改变模型参数进行的模拟证明了 IPH 在斑块不稳定中的重要作用。结果发现，IPH 通过增加坏死核心和减薄纤维帽可以显著加速斑块的脆弱性。此外，MVD 和血管通透性的降低可能通过显著减少 IPH 来减缓斑块不稳定的过程。我们设想，目前的模型及其未来的发展可以作为研究斑块不稳定期间微环境动态变化的有价值的理论平台。
