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1
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Jui E, Kingsley G, Phan HKT, Singampalli KL, Birla RK, Connell JP, Keswani SG, Grande-Allen KJ. Shear Stress Induces a Time-Dependent Inflammatory Response in Human Monocyte-Derived Macrophages. Ann Biomed Eng 2024; 52:2932-2947. [PMID: 39289258 DOI: 10.1007/s10439-024-03546-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 05/10/2024] [Indexed: 09/19/2024]
Abstract
Macrophages are innate immune cells that are known for their extreme plasticity, enabling diverse phenotypes that lie on a continuum. In a simplified model, they switch between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes depending on surrounding microenvironmental cues, which have been implicated in disease outcomes. Although considerable research has been focused on macrophage response to biochemical cues and mechanical signals, there is a scarcity of knowledge surrounding their behavior in response to shear stress. In this study, we applied varying magnitudes of shear stress on human monocyte-derived macrophages (MDMs) using a cone-and-plate viscometer and evaluated changes in morphology, gene expression, protein expression, and cytokine secretion over time. MDMs exposed to shear stress exhibited a rounder morphology compared to statically-cultured controls. RT-qPCR results showed significant upregulation of TNF-α, and analysis of cytokine release revealed increased secretion of IL-8, IL-18, fractalkine, and other chemokines. The upregulation of pro-inflammatory factors was evident with both increasing magnitudes of shear and time. Taken together, these results indicate that prolonged shear exposure induced a pro-inflammatory phenotype in human MDMs. These findings have implications for medical technology development, such as in situ vascular graft design wherein macrophages are exposed to shear and have been shown to affect graft resorption, and in delineating disease pathophysiology, for example to further illuminate the role of macrophages in atherosclerosis where shear is directly related to disease outcome.
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Affiliation(s)
- Elysa Jui
- Department of Bioengineering, Rice University, 6100 Main St, Houston, TX, USA
| | - Griffin Kingsley
- Department of Bioengineering, Rice University, 6100 Main St, Houston, TX, USA
| | - Hong Kim T Phan
- Department of Bioengineering, Rice University, 6100 Main St, Houston, TX, USA
| | - Kavya L Singampalli
- Department of Bioengineering, Rice University, 6100 Main St, Houston, TX, USA
- Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA
| | - Ravi K Birla
- Department of Surgery, Baylor College of Medicine, Houston, TX, USA
- Division of Pediatric Surgery, Department of Surgery, Texas Children's Hospital, Houston, TX, USA
| | - Jennifer P Connell
- Department of Bioengineering, Rice University, 6100 Main St, Houston, TX, USA
| | - Sundeep G Keswani
- Department of Surgery, Baylor College of Medicine, Houston, TX, USA
- Division of Pediatric Surgery, Department of Surgery, Texas Children's Hospital, Houston, TX, USA
| | - K Jane Grande-Allen
- Department of Bioengineering, Rice University, 6100 Main St, Houston, TX, USA.
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2
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Du J, Peng J, Shen X, Li X, Zhong H, Gao Z, Chen M, Qi L, Xie Q. Enhanced external counterpulsation treatment regulates blood flow and wall shear stress metrics in femoral artery: An in vivo study in healthy subjects. J Biomech 2023; 159:111797. [PMID: 37703718 DOI: 10.1016/j.jbiomech.2023.111797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 07/25/2023] [Accepted: 09/05/2023] [Indexed: 09/15/2023]
Abstract
As a non-invasive assisted circulation therapy, enhanced external counterpulsation (EECP) has demonstrated potential in treatment of lower-extremity arterial disease (LEAD). However, the underlying hemodynamic mechanism remains unclear. This study aimed to conduct the first prospective investigation of the EECP-induced responses of blood flow behavior and wall shear stress (WSS) metrics in the femoral artery. Twelve healthy male volunteers were enrolled. A Doppler ultrasound-basedapproach was introduced for the in vivo determination of blood flow in the common femoral artery (CFA) and superficial femoral artery (SFA) during EECP intervention, with incremental treatment pressures ranging from 10 to 40 kPa. Three-dimensional subject-specific numerical models were developed in 6 subjects to quantitatively assess variations in WSS-derived hemodynamic metrics in the femoral bifurcation. A mesh-independence analysis was performed. Our results indicated that, compared to the pre-EECP condition, both the antegrade and retrograde blood flow volumes in the CFA and SFA were significantly augmented during EECP intervention, while the heart rate remained constant. The time average shear stress (TAWSS) over the entire femoral bifurcation increased by 32.41%, 121.30%, 178.24%, and 214.81% during EECP with treatment pressures of 10 kPa, 20 kPa, 30 kPa, and 40 kPa, respectively. The mean relative resident time (RRT) decreased by 24.53%, 61.01%, 69.81%, and 77.99%, respectively. The percentage of area with low TAWSS in the femoral artery dropped to nearly zero during EECP with a treatment pressure greater than or equal to 30 kPa. We suggest that EECP is an effective and non-invasive approach for regulating blood flow and WSS in lower extremity arteries.
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Affiliation(s)
- Jianhang Du
- Medical Research Center, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, China; National Health Commission (NHC) Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou 510080, China.
| | - Junping Peng
- Department of Radiology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, China
| | - Xuelian Shen
- Department of Ultrasound, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, China
| | - Xiaoling Li
- Community Health Service Management Center, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Huiling Zhong
- Medical Research Center, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, China; National Health Commission (NHC) Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou 510080, China
| | - Zhuxuan Gao
- College of Medicine and Biological Information Engineering, Northeastern University, Shenyang 110819, China
| | - Muyan Chen
- College of Medicine and Biological Information Engineering, Northeastern University, Shenyang 110819, China
| | - Lin Qi
- College of Medicine and Biological Information Engineering, Northeastern University, Shenyang 110819, China
| | - Qilian Xie
- Department of Pediatrics, Children's Hospital of Anhui Medical University, Hefei 230051, China
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3
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Zhang S, Zhang Y, Zhang P, Wei Z, Ma M, Wang W, Tong W, Tian F, Hui H, Tian J, Chen Y. Plexin D1 mediates disturbed flow-induced M1 macrophage polarization in atherosclerosis. Heliyon 2023; 9:e17314. [PMID: 37389065 PMCID: PMC10300222 DOI: 10.1016/j.heliyon.2023.e17314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 06/06/2023] [Accepted: 06/13/2023] [Indexed: 07/01/2023] Open
Abstract
Atherosclerosis preferentially develops at bifurcations exposed to disturbed flow. Plexin D1 (PLXND1) responds to mechanical forces and drives macrophage accumulation in atherosclerosis. Here, multiple strategies were used to identify the role of PLXND1 in site-specific atherosclerosis. Using computational fluid dynamics and three-dimensional light-sheet fluorescence-microscopy, the elevated PLXND1 in M1 macrophages was mainly distributed in disturbed flow area of ApoE-/- carotid bifurcation lesions, and visualization of atherosclerosis in vivo was achieved by targeting PLXND1. Subsequently, to simulate the microenvironment of bifurcation lesions in vitro, we co-cultured oxidized low-density lipoprotein (oxLDL)-treated THP-1-derived macrophages with shear-treated human umbilical vein endothelial cells (HUVECs). We found that oscillatory shear induced the increase of PLXND1 in M1 macrophages, and knocking down PLXND1 inhibited M1 polarization. Semaphorin 3E, the ligand of PLXND1 which was highly expressed in plaques, strongly enhanced M1 macrophage polarization via PLXND1 in vitro. Our findings provide insights into pathogenesis in site-specific atherosclerosis that PLXND1 mediates disturbed flow-induced M1 macrophage polarization.
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Affiliation(s)
- Suhui Zhang
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, 100853, China
- Senior Department of Cardiology, The Sixth Medical Center of PLA General Hospital, Beijing, 100048, China
| | - Yingqian Zhang
- Senior Department of Cardiology, The Sixth Medical Center of PLA General Hospital, Beijing, 100048, China
| | - Peng Zhang
- School of Computer and Information Technology, Beijing Jiaotong University, Beijing, 100044, China
| | - Zechen Wei
- CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
- University of Chinese Academy of Sciences, Beijing, 100080, China
| | - Mingrui Ma
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, 100853, China
- Senior Department of Cardiology, The Sixth Medical Center of PLA General Hospital, Beijing, 100048, China
| | - Wei Wang
- Senior Department of Cardiology, The Sixth Medical Center of PLA General Hospital, Beijing, 100048, China
| | - Wei Tong
- Senior Department of Cardiology, The Sixth Medical Center of PLA General Hospital, Beijing, 100048, China
| | - Feng Tian
- Senior Department of Cardiology, The Sixth Medical Center of PLA General Hospital, Beijing, 100048, China
| | - Hui Hui
- CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
- University of Chinese Academy of Sciences, Beijing, 100080, China
| | - Jie Tian
- CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
- Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology of China, Beijing, 100191, China
- Zhuhai Precision Medical Center, Zhuhai People's Hospital, Affiliated with Jinan University, Zhuhai, 519000, China
| | - Yundai Chen
- Senior Department of Cardiology, The Sixth Medical Center of PLA General Hospital, Beijing, 100048, China
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4
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Considerations for analysis of endothelial shear stress and strain in FSI models of atherosclerosis. J Biomech 2021; 128:110720. [PMID: 34482227 DOI: 10.1016/j.jbiomech.2021.110720] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 07/15/2021] [Accepted: 08/23/2021] [Indexed: 11/23/2022]
Abstract
Atherosclerosis is a lipid driven chronic inflammatory disease that is characterized by the formation of plaques at predilection sites. These predilection sites (side branches, curved segments, and bifurcations) have often been associated with disturbed shear stress profiles. However, in addition to shear stress, endothelial cells also experience artery wall strain that could contribute to atherosclerosis progression. Herein, we describe a method to accurately obtain these shear stress and strain profiles. We developed a fluid-structure interaction (FSI) framework for modelling arteries within a commercially available package (Abaqus, version 6.14) that included known prestresses (circumferential, axial and pressure associated). In addition, we co-registered 3D histology to a micro-CT-derived 3D reconstruction of an atherosclerotic carotid artery from a cholesterol-fed ApoE-/- mouse to include the spatial distribution of lipids within a subject-specific model. The FSI model also incorporated a nonlinear hyperelastic material model with regionally-varying properties that distinguished between healthy vessel wall and plaque. FSI predicted a lower shear stress than CFD (~-12%), but further decreases in plaque regions with softer properties (~-24%) were dependent on the approach used to implement the prestresses in the artery wall. When implemented with our new hybrid approach (zero prestresses in regions of lipid deposition), there was significant heterogeneity in endothelial shear stress in the atherosclerotic artery due to variations in stiffness and, in turn, wall strain. In conclusion, when obtaining endothelial shear stress and strain in diseased arteries, a careful consideration of prestresses is necessary. This paper offers a way to implement them.
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5
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Vogl BJ, Niemi NR, Griffiths LG, Alkhouli MA, Hatoum H. Impact of calcific aortic valve disease on valve mechanics. Biomech Model Mechanobiol 2021; 21:55-77. [PMID: 34687365 DOI: 10.1007/s10237-021-01527-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 10/07/2021] [Indexed: 10/20/2022]
Abstract
The aortic valve is a highly dynamic structure characterized by a transvalvular flow that is unsteady, pulsatile, and characterized by episodes of forward and reverse flow patterns. Calcific aortic valve disease (CAVD) resulting in compromised valve function and increased pressure overload on the ventricle potentially leading to heart failure if untreated, is the most predominant valve disease. CAVD is a multi-factorial disease involving molecular, tissue and mechanical interactions. In this review, we aim at recapitulating the biomechanical loads on the aortic valve, summarizing the current and most recent research in the field in vitro, in-silico, and in vivo, and offering a clinical perspective on current strategies adopted to mitigate or approach CAVD.
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Affiliation(s)
- Brennan J Vogl
- Biomedical Engineering Department, Michigan Technological University, 1400 Townsend Dr, Houghton, MI, 49931, USA
| | - Nicholas R Niemi
- Biomedical Engineering Department, Michigan Technological University, 1400 Townsend Dr, Houghton, MI, 49931, USA
| | - Leigh G Griffiths
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | | | - Hoda Hatoum
- Biomedical Engineering Department, Michigan Technological University, 1400 Townsend Dr, Houghton, MI, 49931, USA. .,Health Research Institute, Michigan Technological University, Houghton, MI, USA. .,Center of Biocomputing and Digital Health, Michigan Technological University, Houghton, MI, USA.
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6
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Effect of Subject-Specific, Spatially Reduced, and Idealized Boundary Conditions on the Predicted Hemodynamic Environment in the Murine Aorta. Ann Biomed Eng 2021; 49:3255-3266. [PMID: 34528150 DOI: 10.1007/s10439-021-02851-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Accepted: 08/06/2021] [Indexed: 10/20/2022]
Abstract
Mouse models of atherosclerosis have become effective resources to study atherogenesis, including the relationship between hemodynamics and lesion development. Computational methods aid the prediction of the in vivo hemodynamic environment in the mouse vasculature, but careful selection of inflow and outflow boundary conditions (BCs) is warranted to promote model accuracy. Herein, we investigated the impact of animal-specific versus reduced/idealized flow boundary conditions on predicted blood flow patterns in the mouse thoracic aorta. Blood velocities were measured in the aortic root, arch branch vessel, and descending aorta in ApoE-/- mice using phase-contrast MRI. Computational geometries were derived from micro-CT imaging and combinations of high-fidelity or reduced/idealized MR-derived BCs were applied to predict the bulk flow field and hemodynamic metrics (e.g., wall shear stress, WSS; cross-flow index, CFI). Results demonstrate that pressure-free outlet BCs significantly overestimate outlet flow rates as compared to measured values. When compared to models that incorporate 3-component inlet velocity data [[Formula: see text]] and time-varying outlet mass flow splits [[Formula: see text]] (i.e., high-fidelity model), neglecting in-plane inlet velocity components (i.e., [Formula: see text])) leads to errors in WSS and CFI values ranging from 10 to 30% across the model domain whereas the application of a steady outlet mass flow splits results in negligible differences in these hemodynamics metrics. This investigation highlights that 3-component inlet velocity data and at least steady mass flow splits are required for accurate predictions of flow patterns in the mouse thoracic aorta.
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7
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He G, Kan S, Xu S, Sun X, Li R, Shu W, Chen M. LXN deficiency regulates cytoskeleton remodelling by promoting proteolytic cleavage of Filamin A in vascular endothelial cells. J Cell Mol Med 2021; 25:6815-6827. [PMID: 34085389 PMCID: PMC8278077 DOI: 10.1111/jcmm.16685] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/25/2021] [Accepted: 05/12/2021] [Indexed: 12/19/2022] Open
Abstract
Endothelial cells (ECs) respond to blood shear stress by changing their morphology is important for maintaining vascular homeostasis. Studies have documented a relationship between endothelial cell shape and the stress flow, and however, the mechanism underlying this cytoskeletal rearrangement due to shear stress remains uncertain. In this paper, we demonstrate that laminar shear stress (LSS) significantly reduces latexin (LXN) expression in ECs. By using siRNA and cell imaging, we demonstrated that LXN knockdown results in the morphologic change and F‐actin remodelling just like what LSS does in ECs. We further demonstrate that LXN interacts with Filamin A (FLNA) and regulates FLNA proteolytic cleavage and nuclei translocation. By constructing LXN‐/‐ mice and ApoE‐/‐LXN‐/‐ double knockout mice, we evaluated the effect of LXN knockout on aortic endothelium damage in mice. We found that LXN deficiency significantly improves vascular permeability, vasodilation and atherosclerosis in mice. Our findings provide confident evidence, for the first time, that LXN is a novel regulator for morphological maintenance of ECs, and LXN deficiency has a protective effect on vascular homeostasis. This provides new strategies and drug targets for the treatment of vascular diseases.
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Affiliation(s)
- Guozhang He
- State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin, China.,Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Normal University, Guilin, China
| | - Shuang Kan
- State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin, China.,Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Normal University, Guilin, China
| | - Shaohua Xu
- State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin, China.,Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Normal University, Guilin, China
| | - Xuchen Sun
- State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin, China.,Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Normal University, Guilin, China
| | - Rong Li
- State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin, China.,Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Normal University, Guilin, China
| | - Wei Shu
- College of Biotechnology, Guilin Medical University, Guilin, China
| | - Ming Chen
- State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin, China.,Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Normal University, Guilin, China
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8
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Sangha GS, Goergen CJ, Prior SJ, Ranadive SM, Clyne AM. Preclinical techniques to investigate exercise training in vascular pathophysiology. Am J Physiol Heart Circ Physiol 2021; 320:H1566-H1600. [PMID: 33385323 PMCID: PMC8260379 DOI: 10.1152/ajpheart.00719.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Atherosclerosis is a dynamic process starting with endothelial dysfunction and inflammation and eventually leading to life-threatening arterial plaques. Exercise generally improves endothelial function in a dose-dependent manner by altering hemodynamics, specifically by increased arterial pressure, pulsatility, and shear stress. However, athletes who regularly participate in high-intensity training can develop arterial plaques, suggesting alternative mechanisms through which excessive exercise promotes vascular disease. Understanding the mechanisms that drive atherosclerosis in sedentary versus exercise states may lead to novel rehabilitative methods aimed at improving exercise compliance and physical activity. Preclinical tools, including in vitro cell assays, in vivo animal models, and in silico computational methods, broaden our capabilities to study the mechanisms through which exercise impacts atherogenesis, from molecular maladaptation to vascular remodeling. Here, we describe how preclinical research tools have and can be used to study exercise effects on atherosclerosis. We then propose how advanced bioengineering techniques can be used to address gaps in our current understanding of vascular pathophysiology, including integrating in vitro, in vivo, and in silico studies across multiple tissue systems and size scales. Improving our understanding of the antiatherogenic exercise effects will enable engaging, targeted, and individualized exercise recommendations to promote cardiovascular health rather than treating cardiovascular disease that results from a sedentary lifestyle.
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Affiliation(s)
- Gurneet S Sangha
- Fischell Department of Bioengineering, University of Maryland, College Park, Maryland
| | - Craig J Goergen
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana.,Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana
| | - Steven J Prior
- Department of Kinesiology, University of Maryland School of Public Health, College Park, Maryland.,Baltimore Veterans Affairs Geriatric Research, Education, and Clinical Center, Baltimore, Maryland
| | - Sushant M Ranadive
- Department of Kinesiology, University of Maryland School of Public Health, College Park, Maryland
| | - Alisa M Clyne
- Fischell Department of Bioengineering, University of Maryland, College Park, Maryland
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9
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Cong M, Xu X, Qiu J, Dai S, Chen C, Qian X, Zhang H, Qin S, Zhao H. Influence of malformation of right coronary artery originating from the left sinus in hemodynamic environment. Biomed Eng Online 2020; 19:59. [PMID: 32727522 PMCID: PMC7392689 DOI: 10.1186/s12938-020-00804-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 07/23/2020] [Indexed: 11/11/2022] Open
Abstract
Background The anomalous origin of the right coronary artery (RCA) from the left coronary artery sinus (AORL) is one of the abnormal origins of the coronary arteries. Most of these issues rarely have any effects on human health, but some individuals may exhibit symptoms, such as myocardial ischemia or even sudden death. Recently, researchers have investigated the AORL through clinical cases, but studies based on computational fluid dynamics (CFD) have rarely been reported. In this study, the hemodynamic changes between the normal origin of the RCA and the AORL are compared based on numerical simulation results. Methods Realistic three-dimensional (3D) models of the 16 normal right coronary arteries and 26 abnormal origins of the RCAs were constructed, respectively. The blood flow was numerically simulated using the ANSYS software. This study used a one-way fluid–solid coupling finite element model, wherein the blood is assumed to be an incompressible Newtonian fluid, and the vessel is assumed to be made of an isotropic linear elastic material. Results The cross-sectional area differences between the inlet of the normal group and that of the abnormal group were significant (P < 0.0001). Moreover, there were significant differences in the volumetric flow (P = 0.0001) and pressure (P = 0.0002). Positive correlation exists for the ratio of the cross-sectional area of the RCA to the inlet area of the ascending aorta (AAO), and the ratio of the inlet volumetric flow of the RCA to the volumetric flow of the AAO, in the normal (P = 0.0001, r = 0.8178) and abnormal (P = 0.0033, r = 0.6107) groups. Conclusion This study demonstrates that the cross-sectional area of the AORL inlet may cause ischemia symptoms. The results obtained by this study may contribute to the further understanding of the clinical symptoms of the AORL based on the hemodynamics.
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Affiliation(s)
- Mengyang Cong
- College of Mechanical and Electronic Engineering, Shandong University of Science and Technology, Qingdao, 266590, China
| | - Xingming Xu
- Intelligent Equipment College, Shandong University of Science and Technology, Taian, 271016, China
| | - Jianfeng Qiu
- Department of Radiology, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271016, China.,Center for Medical Engineer Technology Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271016, China
| | - Shun Dai
- Department of Radiology, Shanghai Tong Ren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200120, China
| | - Chuanzhi Chen
- Department of Radiology, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Xiuqing Qian
- Department of Biomedical engineering, Capital Medical University, Beijing, 10060, China
| | - Hongbin Zhang
- College of Mechanical and Electronic Engineering, Shandong University of Science and Technology, Qingdao, 266590, China
| | - Shengxue Qin
- College of Mechanical and Electronic Engineering, Shandong University of Science and Technology, Qingdao, 266590, China.
| | - Huihui Zhao
- Department of Radiology, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271016, China. .,Center for Medical Engineer Technology Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271016, China.
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10
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Adams S, Wuescher LM, Worth R, Yildirim-Ayan E. Mechano-Immunomodulation: Mechanoresponsive Changes in Macrophage Activity and Polarization. Ann Biomed Eng 2019; 47:2213-2231. [PMID: 31218484 PMCID: PMC7043232 DOI: 10.1007/s10439-019-02302-4] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 06/07/2019] [Indexed: 12/31/2022]
Abstract
In recent years, biomaterial- and scaffold-based immunomodulation strategies were implemented in tissue regeneration efforts for manipulating macrophage polarization (a.k.a. phenotype or lineage commitment, or differentiation). Yet, most of our understanding of macrophage phenotype commitment and phagocytic capacity is limited to how physical cues (extracellular matrix stiffness, roughness, and topography) and soluble chemical cues (cytokines and chemokines released from the scaffold) influence macrophage polarization. In the context of immune response-tissue interaction, the mechanical cues experienced by the residing cells within the tissue also play a critical role in macrophage polarization and inflammatory response. However, there is no compiled study discussing the effect of the dynamic mechanical environment around the tissues on macrophage polarization and the innate immune response. The aim of this comprehensive review paper is 2-fold; (a) to highlight the importance of mechanical cues on macrophage lineage commitment and function and (b) to summarize the important studies dedicated to understand how macrophage polarization changes with different mechanical loading modalities. For the first time, this review paper compiles and compartmentalizes the studies investigating the role of dynamic mechanical loading with various modalities, amplitude, and frequency on macrophage differentiation. A deeper understanding of macrophage phenotype in mechanically dominant tissues (i.e. musculoskeletal tissues, lung tissues, and cardiovascular tissues) provides mechanistic insights into the design of mechano-immunomodulatory tissue scaffold for tissue regeneration.
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Affiliation(s)
- Sarah Adams
- Department of Bioengineering, College of Engineering, University of Toledo, Toledo, OH, 43606, USA
| | - Leah M Wuescher
- Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA
| | - Randall Worth
- Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA
| | - Eda Yildirim-Ayan
- Department of Bioengineering, College of Engineering, University of Toledo, Toledo, OH, 43606, USA.
- Department of Orthopaedic Surgery, University of Toledo Medical Center, Toledo, OH, 43614, USA.
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11
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Liu QY, Duan Q, Fu XH, Jiang M, Xia HW, Wan YL. Wall shear stress can improve prediction accuracy for transient ischemic attack. World J Clin Cases 2019; 7:2722-2733. [PMID: 31616688 PMCID: PMC6789401 DOI: 10.12998/wjcc.v7.i18.2722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 08/05/2019] [Accepted: 08/20/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Early prediction of transient ischemic attack (TIA) has important clinical value. To date, systematic studies on clinical, biochemical, and imaging indicators related to carotid atherosclerosis have been carried out to predict the occurrence of TIA. However, their prediction accuracy is limited.
AIM To explore the role of combining wall shear stress (WSS) with conventional predictive indicators in improving the accuracy of TIA prediction.
METHODS A total of 250 patients with atherosclerosis who underwent carotid ultrasonography at Naval Military Medical University Affiliated Gongli Hospital were recruited. Plaque location, plaque properties, stenosis rate, peak systolic velocity, and end diastolic velocity were measured and recorded. The WSS distribution map of the proximal and distal ends of the plaque shoulder was drawn using the shear stress quantitative analysis software, and the average values of WSS were recorded. The laboratory indicators of the subjects were recorded. The patients were followed for 4 years. Patients with TIA were included in a TIA group and the remaining patients were included in a control group. The clinical data, laboratory indicators, and ultrasound characteristics of the two groups were analyzed. Survival curves were plotted by the Kaplan-Meier method. Receiver operating characteristic curves were established to evaluate the accuracy of potential indicators in predicting TIA. Logistic regression model was used to establish combined prediction, and the accuracy of combined predictive indicators for TIA was explored.
RESULTS The intraclass correlation coefficients of the WSS between the proximal and distal ends of the plaque shoulder were 0.976 and 0.993, respectively, which indicated an excellent agreement. At the end of the follow-up, 30 patients suffered TIA (TIA group) and 204 patients did not (control group). Hypertension (P = 0.037), diabetes (P = 0.026), homocysteine (Hcy) (P = 0.022), fasting blood glucose (P = 0.034), plaque properties (P = 0.000), luminal stenosis rate (P = 0.000), and proximal end WSS (P = 0.000) were independent influencing factors for TIA during follow-up. The accuracy of each indicator for predicting TIA individually was not high (area under the curve [AUC] < 0.9). The accuracy of the combined indicator including WSS (AUC = 0.944) was significantly higher than that of the combined indicator without WSS (AUC = 0.856) in predicting TIA (z = 2.177, P = 0.030). The sensitivity and specificity of the combined indicator including WSS were 86.67% and 92.16%, respectively.
CONCLUSION WSS at plaque surface combined with hypertension, diabetes, Hcy, blood glucose, plaque properties, and stenosis rate can significantly improve the accuracy of predicting TIA.
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Affiliation(s)
- Qiu-Yun Liu
- Department of Ultrasound, Naval Military Medical University Affiliated Gongli Hospital, Shanghai 200000, China
| | - Qi Duan
- Department of Ultrasound, Shanghai Hemujia Hospital, Shanghai 200000, China
| | - Xiao-Hong Fu
- Department of Ultrasound, Naval Military Medical University Affiliated Gongli Hospital, Shanghai 200000, China
| | - Mei Jiang
- Department of Neurology, Naval Military Medical University Affiliated Gongli Hospital, Shanghai 200000, China
| | - Hong-Wei Xia
- Department of Ultrasound, Naval Military Medical University Affiliated Gongli Hospital, Shanghai 200000, China
| | - Yong-Lin Wan
- Department of Ultrasound, Naval Military Medical University Affiliated Gongli Hospital, Shanghai 200000, China
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12
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Aslanidou L, Ferraro M, Lovric G, Bersi MR, Humphrey JD, Segers P, Trachet B, Stergiopulos N. Co-localization of microstructural damage and excessive mechanical strain at aortic branches in angiotensin-II-infused mice. Biomech Model Mechanobiol 2019; 19:81-97. [PMID: 31273562 DOI: 10.1007/s10237-019-01197-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 06/26/2019] [Indexed: 02/07/2023]
Abstract
Animal models of aortic aneurysm and dissection can enhance our limited understanding of the etiology of these lethal conditions particularly because early-stage longitudinal data are scant in humans. Yet, the pathogenesis of often-studied mouse models and the potential contribution of aortic biomechanics therein remain elusive. In this work, we combined micro-CT and synchrotron-based imaging with computational biomechanics to estimate in vivo aortic strains in the abdominal aorta of angiotensin-II-infused ApoE-deficient mice, which were compared with mouse-specific aortic microstructural damage inferred from histopathology. Targeted histology showed that the 3D distribution of micro-CT contrast agent that had been injected in vivo co-localized with precursor vascular damage in the aortic wall at 3 days of hypertension, with damage predominantly near the ostia of the celiac and superior mesenteric arteries. Computations similarly revealed higher mechanical strain in branching relative to non-branching regions, thus resulting in a positive correlation between high strain and vascular damage in branching segments that included the celiac, superior mesenteric, and right renal arteries. These results suggest a mechanically driven initiation of damage at these locations, which was supported by 3D synchrotron imaging of load-induced ex vivo delaminations of angiotensin-II-infused suprarenal abdominal aortas. That is, the major intramural delamination plane in the ex vivo tested aortas was also near side branches and specifically around the celiac artery. Our findings thus support the hypothesis of an early mechanically mediated formation of microstructural defects at aortic branching sites that subsequently propagate into a macroscopic medial tear, giving rise to aortic dissection in angiotensin-II-infused mice.
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Affiliation(s)
- Lydia Aslanidou
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
| | - Mauro Ferraro
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Goran Lovric
- Centre d'Imagerie BioMédicale, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Swiss Light Source, Paul Scherrer Institute, Villigen, Switzerland
| | - Matthew R Bersi
- Department of Biomedical Engineering, Yale University, New Haven, USA
- Department of Biomedical Engineering, Vanderbilt University, Nashville, USA
| | - Jay D Humphrey
- Department of Biomedical Engineering, Yale University, New Haven, USA
| | | | - Bram Trachet
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- bioMMeda, Ghent University, Ghent, Belgium
| | - Nikos Stergiopulos
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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13
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Modern Concepts in Regenerative Therapy for Ischemic Stroke: From Stem Cells for Promoting Angiogenesis to 3D-Bioprinted Scaffolds Customized via Carotid Shear Stress Analysis. Int J Mol Sci 2019; 20:ijms20102574. [PMID: 31130624 PMCID: PMC6566983 DOI: 10.3390/ijms20102574] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 05/20/2019] [Accepted: 05/22/2019] [Indexed: 02/06/2023] Open
Abstract
Ischemic stroke is associated with a tremendous economic and societal burden, and only a few therapies are currently available for the treatment of this devastating disease. The main therapeutic approaches used nowadays for the treatment of ischemic brain injury aim to achieve reperfusion, neuroprotection and neurorecovery. Therapeutic angiogenesis also seems to represent a promising tool to improve the prognosis of cerebral ischemia. This review aims to present the modern concepts and the current status of regenerative therapy for ischemic stroke and discuss the main results of major clinical trials addressing the effectiveness of stem cell therapy for achieving neuroregeneration in ischemic stroke. At the same time, as a glimpse into the future, this article describes modern concepts for stroke prevention, such as the implantation of bioprinted scaffolds seeded with stem cells, whose 3D geometry is customized according to carotid shear stress.
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14
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Gallo D, Bijari PB, Morbiducci U, Qiao Y, Xie YJ, Etesami M, Habets D, Lakatta EG, Wasserman BA, Steinman DA. Segment-specific associations between local haemodynamic and imaging markers of early atherosclerosis at the carotid artery: an in vivo human study. J R Soc Interface 2018; 15:rsif.2018.0352. [PMID: 30305419 DOI: 10.1098/rsif.2018.0352] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 09/10/2018] [Indexed: 12/16/2022] Open
Abstract
Low and oscillatory wall shear stress (WSS) has long been hypothesized as a risk factor for atherosclerosis; however, evidence has been inferred primarily from model and post-mortem studies, or clinical studies of patients with already-developed plaques. This study aimed to identify associations between local haemodynamic and imaging markers of early atherosclerosis. Comprehensive magnetic resonance imaging allowed quantification of contrast enhancement (CE) (a marker of endothelial dysfunction) and vessel wall thickness at two distinct segments: the internal carotid artery bulb and the common carotid artery (CCA). Strict criteria were applied to a large dataset to exclude inward remodelling, resulting in 41 cases for which personalized computational fluid dynamic simulations were performed. After controlling for cardiovascular risk factors, bulb wall thickening was found to be weakly, but not significantly, associated with oscillatory WSS. CE at the bulb was significantly associated with low WSS (p < 0.001) and low flow helicity (p < 0.05). No significant associations were found for the CCA segment. Local haemodynamics at the bulb were significantly correlated with blood flow rates and heart rates, but not carotid bifurcation geometry (flare and curvature). Therefore low, but not oscillatory, WSS is an early independent marker of atherosclerotic changes preceding intimal thickening at the carotid bulb.
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Affiliation(s)
- Diego Gallo
- Biomedical Simulation Lab, Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario, Canada.,PolitoMed Lab, Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
| | - Payam B Bijari
- Biomedical Simulation Lab, Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Umberto Morbiducci
- PolitoMed Lab, Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
| | - Ye Qiao
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yuanyuan Joyce Xie
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Maryam Etesami
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Damiaan Habets
- Biomedical Simulation Lab, Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Edward G Lakatta
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIA, Baltimore, MD, USA
| | - Bruce A Wasserman
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - David A Steinman
- Biomedical Simulation Lab, Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario, Canada
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15
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Giordanetto F, Knerr L, Nordberg P, Pettersen D, Selmi N, Beisel HG, de la Motte H, Månsson Å, Dahlström M, Broddefalk J, Saarinen G, Klingegård F, Hurt-Camejo E, Rosengren B, Wikström J, Wågberg M, Brengdahl J, Rohman M, Sandmark J, Åkerud T, Roth RG, Jansen F, Ahlqvist M. Design of Selective sPLA 2-X Inhibitor (-)-2-{2-[Carbamoyl-6-(trifluoromethoxy)-1 H-indol-1-yl]pyridine-2-yl}propanoic Acid. ACS Med Chem Lett 2018; 9:600-605. [PMID: 30034586 DOI: 10.1021/acsmedchemlett.7b00507] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 06/23/2018] [Indexed: 11/28/2022] Open
Abstract
A lead generation campaign identified indole-based sPLA2-X inhibitors with a promising selectivity profile against other sPLA2 isoforms. Further optimization of sPLA2 selectivity and metabolic stability resulted in the design of (-)-17, a novel, potent, and selective sPLA2-X inhibitor with an exquisite pharmacokinetic profile characterized by high absorption and low clearance, and low toxicological risk. Compound (-)-17 was tested in an ApoE-/- murine model of atherosclerosis to evaluate the effect of reversible, pharmacological sPLA2-X inhibition on atherosclerosis development. Despite being well tolerated and achieving adequate systemic exposure of mechanistic relevance, (-)-17 did not significantly affect circulating lipid and lipoprotein biomarkers and had no effect on coronary function or histological markers of atherosclerosis.
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16
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Xing R, Moerman AM, Ridwan Y, Daemen MJ, van der Steen AFW, Gijsen FJH, van der Heiden K. Temporal and spatial changes in wall shear stress during atherosclerotic plaque progression in mice. ROYAL SOCIETY OPEN SCIENCE 2018; 5:171447. [PMID: 29657758 PMCID: PMC5882682 DOI: 10.1098/rsos.171447] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 02/07/2018] [Indexed: 05/03/2023]
Abstract
Wall shear stress (WSS) is involved in atherosclerotic plaque initiation, yet its role in plaque progression remains unclear. We aimed to study (i) the temporal and spatial changes in WSS over a growing plaque and (ii) the correlation between WSS and plaque composition, using animal-specific data in an atherosclerotic mouse model. Tapered casts were placed around the right common carotid arteries (RCCA) of ApoE-/- mice. At 5, 7 and 9 weeks after cast placement, RCCA geometry was reconstructed using contrast-enhanced micro-CT. Lumen narrowing was observed in all mice, indicating the progression of a lumen intruding plaque. Next, we determined the flow rate in the RCCA of each mouse using Doppler Ultrasound and computed WSS at all time points. Over time, as the plaque developed and further intruded into the lumen, absolute WSS significantly decreased. Finally at week 9, plaque composition was histologically characterized. The proximal part of the plaque was small and eccentric, exposed to relatively lower WSS. Close to the cast a larger and concentric plaque was present, exposed to relatively higher WSS. Lower WSS was significantly correlated to the accumulation of macrophages in the eccentric plaque. When pooling data of all animals, correlation between WSS and plaque composition was weak and no longer statistically significant. In conclusion, our data showed that in our mouse model absolute WSS strikingly decreased during disease progression, which was significantly correlated to plaque area and macrophage content. Besides, our study demonstrates the necessity to analyse individual animals and plaques when studying correlations between WSS and plaque composition.
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Affiliation(s)
- R. Xing
- Department of Biomedical Engineering, Thorax Center, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - A. M. Moerman
- Department of Biomedical Engineering, Thorax Center, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Y. Ridwan
- Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - M. J. Daemen
- Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
| | - A. F. W. van der Steen
- Department of Biomedical Engineering, Thorax Center, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - F. J. H. Gijsen
- Department of Biomedical Engineering, Thorax Center, Erasmus University Medical Center, Rotterdam, The Netherlands
- Authors for correspondence: F. J. H. Gijsen e-mail:
| | - K. van der Heiden
- Department of Biomedical Engineering, Thorax Center, Erasmus University Medical Center, Rotterdam, The Netherlands
- Authors for correspondence: K. van der Heiden e-mail:
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17
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A multiphysics approach for modeling early atherosclerosis. Biomech Model Mechanobiol 2017; 17:617-644. [PMID: 29159532 DOI: 10.1007/s10237-017-0982-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 11/04/2017] [Indexed: 01/03/2023]
Abstract
This work is devoted to the development of a mathematical model of the early stages of atherosclerosis incorporating processes of all time scales of the disease and to show their interactions. The cardiovascular mechanics is modeled by a fluid-structure interaction approach coupling a non-Newtonian fluid to a hyperelastic solid undergoing anisotropic growth and a change of its constitutive equation. Additionally, the transport of low-density lipoproteins and its penetration through the endothelium is considered by a coupled set of advection-diffusion-reaction equations. Thereby, the permeability of the endothelium is wall-shear stress modulated resulting in a locally varying accumulation of foam cells triggering a novel growth and remodeling formulation. The model is calibrated and applied to an murine-specific case study, and a qualitative validation of the computational results is performed. The model is utilized to further investigate the influence of the pulsatile blood flow and the compliance of the artery wall to the atherosclerotic process. The computational results imply that the pulsatile blood flow is crucial, whereas the compliance of the aorta has only a minor influence on atherosclerosis. Further, it is shown that the novel model is capable to produce a narrowing of the vessel lumen inducing an adaption of the endothelial permeability pattern.
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18
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Quantifying the influence of oscillatory flow disturbances on blood flow. J Theor Biol 2017; 430:195-206. [DOI: 10.1016/j.jtbi.2017.07.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Revised: 05/29/2017] [Accepted: 07/11/2017] [Indexed: 11/23/2022]
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19
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Pedrigi RM, Mehta VV, Bovens SM, Mohri Z, Poulsen CB, Gsell W, Tremoleda JL, Towhidi L, de Silva R, Petretto E, Krams R. Influence of shear stress magnitude and direction on atherosclerotic plaque composition. ROYAL SOCIETY OPEN SCIENCE 2016; 3:160588. [PMID: 27853578 PMCID: PMC5099003 DOI: 10.1098/rsos.160588] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 09/19/2016] [Indexed: 05/19/2023]
Abstract
The precise flow characteristics that promote different atherosclerotic plaque types remain unclear. We previously developed a blood flow-modifying cuff for ApoE-/- mice that induces the development of advanced plaques with vulnerable and stable features upstream and downstream of the cuff, respectively. Herein, we sought to test the hypothesis that changes in flow magnitude promote formation of the upstream (vulnerable) plaque, whereas altered flow direction is important for development of the downstream (stable) plaque. We instrumented ApoE-/- mice (n = 7) with a cuff around the left carotid artery and imaged them with micro-CT (39.6 µm resolution) eight to nine weeks after cuff placement. Computational fluid dynamics was then performed to compute six metrics that describe different aspects of atherogenic flow in terms of wall shear stress magnitude and/or direction. In a subset of four imaged animals, we performed histology to confirm the presence of advanced plaques and measure plaque length in each segment. Relative to the control artery, the region upstream of the cuff exhibited changes in shear stress magnitude only (p < 0.05), whereas the region downstream of the cuff exhibited changes in shear stress magnitude and direction (p < 0.05). These data suggest that shear stress magnitude contributes to the formation of advanced plaques with a vulnerable phenotype, whereas variations in both magnitude and direction promote the formation of plaques with stable features.
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Affiliation(s)
- Ryan M. Pedrigi
- Department of Bioengineering, Imperial College London, London, UK
| | - Vikram V. Mehta
- Department of Bioengineering, Imperial College London, London, UK
| | - Sandra M. Bovens
- Department of Bioengineering, Imperial College London, London, UK
| | - Zahra Mohri
- Department of Bioengineering, Imperial College London, London, UK
| | | | - Willy Gsell
- MRC-Clinical Sciences Centre, Imperial College London, London, UK
- Biomedical MRI, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Jordi L. Tremoleda
- MRC-Clinical Sciences Centre, Imperial College London, London, UK
- Centre for Trauma Sciences, Queen Mary University of London, London, UK
| | - Leila Towhidi
- Department of Bioengineering, Imperial College London, London, UK
| | - Ranil de Silva
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Enrico Petretto
- MRC-Clinical Sciences Centre, Imperial College London, London, UK
- Duke-NUS Medical School, Singapore, Republic of Singapore
| | - Rob Krams
- Department of Bioengineering, Imperial College London, London, UK
- Author for correspondence: Rob Krams e-mail:
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20
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Gelfand BD, Ambati J. A Revised Hemodynamic Theory of Age-Related Macular Degeneration. Trends Mol Med 2016; 22:656-670. [PMID: 27423265 DOI: 10.1016/j.molmed.2016.06.009] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Revised: 06/16/2016] [Accepted: 06/16/2016] [Indexed: 12/16/2022]
Abstract
Age-related macular degeneration (AMD) afflicts one out of every 40 individuals worldwide, causing irreversible central blindness in millions. The transformation of various tissue layers within the macula in the retina has led to competing conceptual models of the molecular pathways, cell types, and tissues responsible for the onset and progression of AMD. A model that has persisted for over 6 decades is the hemodynamic, or vascular theory of AMD progression, which states that vascular dysfunction of the choroid underlies AMD pathogenesis. Here, we re-evaluate this hypothesis in light of recent advances on molecular, anatomic, and hemodynamic changes underlying choroidal dysfunction in AMD. We propose an updated, detailed model of hemodynamic dysfunction as a mechanism of AMD development and progression.
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Affiliation(s)
- Bradley D Gelfand
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Biomedical Engineering, University of Kentucky, Lexington, KY, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY, USA
| | - Jayakrishna Ambati
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Physiology, University of Kentucky, Lexington, KY, USA.
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