Abstract
BackgroundGrowing experimental evidence has identified neovascularization from the adventitial vasa vasorum and induced intraplaque hemorrhage (IPH) as critical indicators during the development of vulnerable atherosclerotic plaques. In this study, we propose a mathematical model incorporating intraplaque angiogenesis and hemodynamic calculation of the microcirculation, to obtain the quantitative evaluation of the influences of intraplaque neovascularization and hemorrhage on vulnerable plaque development. A two-dimensional nine-point model of angiogenic microvasculature is generated based on the histology of a patient’s carotid plaque. The intraplaque angiogenesis model includes three key cells (endothelial cells, smooth muscle cells, and macrophages) and three key chemical factors (vascular endothelial growth factors, extracellular matrix, and matrix metalloproteinase), which densities and concentrations are described by a series of reaction–diffusion equations. The hemodynamic calculation by coupling the intravascular blood flow, the extravascular plasma flow, and the transvascular transport is carried out on the generated angiogenic microvessel network. We then define the IPH area by using the plasma concentration in the interstitial tissue, as well as the extravascular transport across the capillary wall.ResultsThe simulational results reproduce a series of pathophysiological phenomena during the atherosclerotic plaque progression. It is found that the high microvessel density region at the shoulder areas and the extravascular flow across the leaky wall of the neovasculature contribute to the IPH observed widely in vulnerable plaques. The simulational results are validated by both the in vivo MR imaging data and in vitro experimental observations and show significant consistency in quantity ground. Moreover, the sensitivity analysis of model parameters reveals that the IPH area and extent can be reduced significantly by decreasing the MVD and the wall permeability of the neovasculature.ConclusionsThe current quantitative model could help us to better understand the roles of microvascular and intraplaque hemorrhage during the carotid plaque progression.
Highlights
Atherosclerosis is the process in which plaques, consisting of lipoproteins, monocyte/ macrophages, vascular smooth muscle cells (SMCs) and platelets, are built up in the injured walls of arteries as a chronic inflammatory response
The simulational results reproduce a series of pathophysiological phenomena during the atherosclerotic plaque progression, such as the high microvessel density region at the shoulder areas, the enlarged necrotic core, and the intraplaque hemorrhage (IPH) caused by the extravascular plasma flow across the leaky wall of the neovasculature
As time passing by and with increased neovessels, intravascular pressure PV decreases associate with intravascular velocity UV monotonously from the vasa vasorum of adventitia to the necrotic region
Summary
Atherosclerosis is the process in which plaques, consisting of lipoproteins, monocyte/ macrophages, vascular smooth muscle cells (SMCs) and platelets, are built up in the injured walls of arteries as a chronic inflammatory response. As the atherosclerotic plaque develops, a hypoxic microenvironment in the plaque lesion is forming due to the increased oxygen consumption caused by high metabolic active cells (such as macrophages). This pathological microenvironment will trigger intraplaque neovascularization by upregulation of proangiogenic factors, such as vascular endothelial growth factors (VEGFs). The angiogenic microvessels generated from the adventitial vasa vasorum transport blood-borne components including inflammatory cells and lipoproteins into the lesion, which can exacerbate the lipid and inflammatory microenvironment inside the plaques [1, 2]. Growing experimental evidence has identified neovascularization from the adventitial vasa vasorum and induced intraplaque hemorrhage (IPH) as critical indicators during the development of vulnerable atherosclerotic plaques. We define the IPH area by using the plasma concentration in the interstitial tissue, as well as the extravascular transport across the capillary wall
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