Smooth muscle cells affect differential nanoparticle accumulation in disturbed blood flow-induced murine atherosclerosis (original) (raw)
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ACS Nano, 2019
Atherosclerosis is associated with a compromised endothelial barrier, facilitating the accumulation of immune cells and macromolecules in atherosclerotic lesions. In this study, we investigate endothelial barrier integrity and the enhanced permeability and retention (EPR) effect during atherosclerosis progression and therapy in Apoe −/− mice using hyaluronan nanoparticles (HA-NPs). Utilizing ultrastructural and en face plaque imaging, we uncover a significantly decreased junction continuity in the atherosclerotic plaquecovering endothelium compared to the normal vessel wall, indicative of disrupted endothelial barrier. Intriguingly, the plaque advancement had a positive effect on junction stabilization, which correlated with a 3-fold lower accumulation of in vivo administrated HA-NPs in advanced plaques compared to early counterparts. Furthermore, by using superresolution and correlative light and electron microscopy, we trace nanoparticles in the plaque microenvironment. We find nanoparticle-enriched endothelial junctions, containing 75% of detected HA-NPs, and a high HA-NP accumulation in the endothelium-underlying extracellular matrix, which suggest an endothelial junctional traffic of HA-NPs to the plague. Finally, we probe the EPR effect by HA-NPs in the context of metabolic therapy with a glycolysis inhibitor, 3PO, proposed as a vascular normalizing strategy. The observed trend of attenuated HA-NP uptake in aortas of 3PO-treated mice coincides with the endothelial silencing activity of 3PO, demonstrated in vitro. Interestingly, the therapy also reduced the plaque inflammatory burden, while activating macrophage metabolism. Our findings shed light on natural limitations of nanoparticle accumulation in atherosclerotic plaques and provide mechanistic insight into nanoparticle trafficking across continued...
ACS Nano, 2015
Atherosclerosis is a major cause of global morbidity and mortality that could benefit from novel targeted therapeutics. Recent studies have shown efficient and local drug delivery with nanoparticles, although the nanoparticle targeting mechanism for atherosclerosis has not yet been fully elucidated. Here we used in vivo and ex vivo multimodal imaging to examine permeability of the vessel wall and atherosclerotic plaque accumulation of fluorescently labeled liposomal nanoparticles in a rabbit model. We found a strong correlation between permeability as established by in vivo dynamic contrast enhanced magnetic resonance imaging and nanoparticle plaque accumulation with subsequent nanoparticle distribution throughout the vessel wall. These key observations will enable the development of nanotherapeutic strategies for atherosclerosis.
2016
Atherosclerosis may be triggered by an elevated net transport of lipid-carrying macromolecules from plasma into the arterial wall. We hypothesised that whether lesions are of the thin-cap fibroatheroma (TCFA) type or are less fatty and more fibrous depends on the degree of elevation of transport, with greater uptake leading to the former. We further hypothesised that the degree of elevation can depend on haemodynamic wall shear stress characteristics and nitric oxide synthesis. Placing a tapered cuff around the carotid artery of apolipoprotein E-/- mice modifies patterns of shear stress and eNOS expression, and triggers lesion development at the upstream and downstream cuff margins; upstream but not downstream lesions resemble the TCFA. We measured wall uptake of a macromolecular tracer in the carotid artery of C57bl/6 mice after cuff placement. Uptake was elevated in the regions that develop lesions in hyperlipidaemic mice and was significantly more elevated where plaques of the TC...
Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 2011
An estimated 16 million people in the United States have coronary artery disease (CAD), and approximately 325,000 people die annually from cardiac arrest. About two-thirds of unexpected cardiac deaths occur without prior recognition of cardiac disease. A vast majority of these deaths are attributable to the rupture of 'vulnerable atherosclerotic plaques'. Clinically, plaque vulnerability is typically assessed through imaging techniques, and ruptured plaques leading to acute myocardial infarction are treated through angioplasty or stenting. Despite significant advances, it is clear that current imaging methods are insufficiently capable for elucidating plaque composition-which is a key determinant of vulnerability. Further, the exciting improvement in the treatment of CAD afforded by stenting procedures has been buffered by significant undesirable host-implant effects, including restenosis and late thrombosis. Nanotechnology has led to some potential solutions to these problems by yielding constructs that interface with plaque cellular components at an unprecedented size scale. By leveraging the innate ability of macrophages to phagocytose nanoparticles, contrast agents can now be targeted to plaque inflammatory activity. Improvements in nano-patterning procedures have now led to increased ability to regenerate tissue isotropy directly on stents, enabling gradual regeneration of normal, physiologic vascular structures. Advancements in immunoassay technologies promise lower costs for biomarker measurements, and in the near future, may enable the addition of routine blood testing to the clinician's toolbox-decreasing the costs of atherosclerosis-related medical care. These are merely three examples among many stories of how nanotechnology continues to promise advances in the diagnosis and treatment of vulnerable atherosclerotic plaques.
Nanoparticle uptake by macrophages in vulnerable plaques for atherosclerosis diagnosis
Journal of biophotonics, 2015
The composition of atherosclerotic (AS) plaques is crucial concerning rupture, thrombosis and clinical events. Two plaque types are distinguished: stable and vulnerable plaques. Vulnerable plaques are rich in inflammatory cells, mostly only M1 macrophages, and are highly susceptible to rupture. These plaques represent a high risk particularly with the standard invasive diagnosis by coronary angiography. So far there are no non-invasive low-risk clinical approaches available to detect and distinguish AS plaque types in vivo. The perspective review introduces a whole work-flow for a novel approach for non-invasive detection and classification of AS plaques using the diffusion reflection method with gold nanoparticle loaded macrophages in combination with flow and image cytometric analysis for quality assurance. Classical biophotonic methods for AS diagnosis are summarized. Phenotyping of monocytes and macrophages are discussed for specific subset labelling by nanomaterials, as well as...
PLoS ONE, 2014
Atherosclerosis may be triggered by an elevated net transport of lipid-carrying macromolecules from plasma into the arterial wall. We hypothesised that whether lesions are of the thin-cap fibroatheroma (TCFA) type or are less fatty and more fibrous depends on the degree of elevation of transport, with greater uptake leading to the former. We further hypothesised that the degree of elevation can depend on haemodynamic wall shear stress characteristics and nitric oxide synthesis. Placing a tapered cuff around the carotid artery of apolipoprotein E -/-mice modifies patterns of shear stress and eNOS expression, and triggers lesion development at the upstream and downstream cuff margins; upstream but not downstream lesions resemble the TCFA. We measured wall uptake of a macromolecular tracer in the carotid artery of C57bl/6 mice after cuff placement. Uptake was elevated in the regions that develop lesions in hyperlipidaemic mice and was significantly more elevated where plaques of the TCFA type develop. Computational simulations and effects of reversing the cuff orientation indicated a role for solid as well as fluid mechanical stresses. Inhibiting NO synthesis abolished the difference in uptake between the upstream and downstream sites. The data support the hypothesis that excessively elevated wall uptake of plasma macromolecules initiates the development of the TCFA, suggest that such uptake can result from solid and fluid mechanical stresses, and are consistent with a role for NO synthesis. Modification of wall transport properties might form the basis of novel methods for reducing plaque rupture. OPEN ACCESS Citation: Mohri Z, Rowland EM, Clarke LA, De Luca A, Peiffer V, et al. (2014) Elevated Uptake of Plasma Macromolecules by Regions of Arterial Wall Predisposed to Plaque Instability in a Mouse Model. PLoS ONE 9(12): e115728.
The Therapeutic Potential of Nanoparticles to Reduce Inflammation in Atherosclerosis
2019
Chronic inflammation is one of the main determinants of atherogenesis. The traditional medications for treatment of atherosclerosis are not very efficient in targeting atherosclerotic inflammation. Most of these drugs are non-selective, anti-inflammatory and immunosuppressive agents that have adverse effects and very limited anti-atherosclerotic effects, which limits their systemic administration. New approaches using nanoparticles have been investigated to specifically deliver therapeutic agents directly on atherosclerotic lesions. The use of drug delivery systems, such as polymeric nanoparticles, liposomes, and carbon nanotubes are attractive strategies, but some limitations exist. For instance, nanoparticles may alter the drug kinetics, based on the pathophysiological mechanisms of the diseases. In this review, we will update pathophysiological evidence for the use of nanoparticles to reduce inflammation and potentially prevent atherogenesis in different experimental models.
Advanced Healthcare Materials, 2019
This narrowed vessel leads to changes in the blood flow pattern. The average shear stress is 15 dyn cm −2 in a healthy coronary artery, which can be elevated to 70-100 dyn cm −2 or even higher by such blockages at the site of advanced lesions. [5] In addition, atherosclerosis preferentially develops within the branching and curved sites of the artery and is influenced by low and oscillatory shear stress (OSS) that mediates low-density lipoprotein (LDL) uptake in endothelial cells. This indicates that hemodynamics plays an important role in the establishment of atherosclerosis. [6] Atherosclerosis starts to develop in the early teenage stage and evolves thereafter. Regardless of the similar progression of atherosclerosis in different races, genders, and geographic locations, the rate of progression in atherosclerosis is faster in patients with risk factors such as hypertension, tobacco smoking, diabetes mellitus, obesity, and genetic inclination. [7] At the cellular level, the endothelium plays key roles in protecting blood vessel walls, participating in inflammatory reactions, secreting proteins on its surface to prevent blood clotting, and developing new blood vessels (angiogenesis). [8,9] Atherosclerosis can be triggered when the endothelium is damaged by high blood pressure (hypertension) [10] and toxins (e.g., smoking [11] and high glucose levels or hyperglycemia). [12] The process is accelerated if there is insufficient high-density lipoprotein (HDL) to remove cholesterol from tissues and carry it back to the liver, known as reverse cholesterol transport (RCT). [13] High ratio of LDL and HDL (more than 3:1) induces high levels of cholesterol in the blood or hypercholesterolemia, which may trigger endothelial dysfunction and promote the accumulation of LDL in the sub-endothelial space. [14-16] The injured or dysfunctional endothelium expresses various adhesion molecules, including endothelial selectin (E-selectin), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), which can capture monocytes and allow them to extravasate into the tunica intima (subendothelial space). [17,18] Free radicals, especially superoxide anions, are released from the damaged endothelium and macrophages in response to LDL accumulation. [19,20] The excessive generation of reactive oxygen species (ROS) promotes oxidative stress [21] and the formation of oxidized LDL (Ox-LDL). [22] The dysfunctional endothelium releases macrophage colony stimulating factor (M-CSF)/colony stimulating factor-1 (CSF-1) that can differentiate monocytes into macrophages. [23,24] These Atherosclerosis is the root of approximately one-third of global mortalities. Nanotechnology exhibits splendid prospects to combat atherosclerosis at the molecular level by engineering smart nanoagents with versatile functionalizations. Significant advances in nanoengineering enable nanoagents to autonomously navigate in the bloodstream, escape from biological barriers, and assemble with their nanocohort at the targeted lesion. The assembly of nanoagents with endogenous and exogenous stimuli breaks down their shells, facilitates intracellular delivery, releases their cargo to kill the corrupt cells, and gives imaging reports. All these improvements pave the way toward personalized medicine for atherosclerosis. This review systematically summarizes the recent advances in stimuli-responsive nanoagents for atherosclerosis management and its progress in clinical trials.
Probing nanoparticle translocation across the permeable endothelium in experimental atherosclerosis
Proceedings of the National Academy of Sciences, 2014
Significance This study shows that an endothelialized microfluidic chip with controllable permeability can serve as a model for nanoparticle translocation across the permeable endothelium. Integration of this in vitro model and an in vivo rabbit model revealed that the extravasation of nanoparticles across the endothelium in atherosclerotic plaques depends on microvascular permeability. This approach represents a unique method for the assessment of nanoparticle behavior across the atherosclerotic endothelium, and may also serve as a valuable tool to study nanomedicine accumulation in a variety of other diseases.