Abstract:Angiotensin (Ang) II contributes to the development of atherosclerosis, while Ang-(1–7) has atheroprotective actions. Accordingly, angiotensin-converting enzyme 2 (ACE2), which breaks-down Ang II and forms Ang-(1–7), has been suggested as a target against atherosclerosis. Here we investigated the actions of diminazene, a recently developed ACE2 activator compound, in a model of vulnerable atherosclerotic plaque. Atherosclerotic plaque formation was induced in the carotid artery of ApoE-deficient mice by a shea… Show more
“…Our previous studies demonstrated that plaques in these vessel segments exhibited advanced features and resembled vulnerable and stable plaque phenotypes, respectively [7–16]. In the vessel segment upstream of the cuff outside of the plaque region, LSI was the dominant metric.…”
Section: Discussionmentioning
confidence: 92%
“…Plaques were present over nearly the entire downstream segment with an average length of 1.2 ± 0.1 mm. Previous work established that plaques upstream of the cuff have vulnerable features, whereas those downstream more closely resemble stable lesions [7–16]. Figure 3.Representative histological sections from the instrumented and contralateral control arteries of a representative mouse at nine weeks, stained for lipids.…”
Section: Resultsmentioning
confidence: 99%
“…In addition, upstream plaques had a higher concentration of lipids, and matrix metalloproteinases overlaid by a thin and inflamed fibrous cap, similar to vulnerable plaques in humans (as determined by an independent expert human pathologist [7]), whereas downstream plaques resembled a more stable plaque phenotype [7]. This model has been shown to reproducibly promote the formation of advanced plaques with vulnerable and stable features in many additional studies by us [8–12] and others [13–16]. …”
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.
“…Our previous studies demonstrated that plaques in these vessel segments exhibited advanced features and resembled vulnerable and stable plaque phenotypes, respectively [7–16]. In the vessel segment upstream of the cuff outside of the plaque region, LSI was the dominant metric.…”
Section: Discussionmentioning
confidence: 92%
“…Plaques were present over nearly the entire downstream segment with an average length of 1.2 ± 0.1 mm. Previous work established that plaques upstream of the cuff have vulnerable features, whereas those downstream more closely resemble stable lesions [7–16]. Figure 3.Representative histological sections from the instrumented and contralateral control arteries of a representative mouse at nine weeks, stained for lipids.…”
Section: Resultsmentioning
confidence: 99%
“…In addition, upstream plaques had a higher concentration of lipids, and matrix metalloproteinases overlaid by a thin and inflamed fibrous cap, similar to vulnerable plaques in humans (as determined by an independent expert human pathologist [7]), whereas downstream plaques resembled a more stable plaque phenotype [7]. This model has been shown to reproducibly promote the formation of advanced plaques with vulnerable and stable features in many additional studies by us [8–12] and others [13–16]. …”
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.
“…ApoE −/− male mice in C57BL/6J background (n = 40) were purchased from Jackson Laboratories (Les Oncins, France) and, at 15 weeks old, received Western‐type diet consisting of 15% (wt/wt) cocoa butter and 0.25% (wt/wt) cholesterol (Diet W; abDiets) for the entire experimental period of 11 weeks. Atherosclerotic plaques with different phenotypes were induced in the carotid artery by modifying the local pattern of shear stress as previously described . Briefly, after a 2‐week western diet adaptation period, a shear stress modifier device, called “cast,” was placed around the right carotid artery.…”
Section: Methodsmentioning
confidence: 99%
“…Immunohistochemistry was performed to assess the intraplaque expression of MMP‐9, as well as macrophage and neutrophil infiltration. As described elsewhere, LSS‐ and OSS‐carotid regions and aortic sinus were serially cut in 7 μm transverse sections (11 sections per staining separated by 45 μm from each other), fixed in acetone and immunostained with specific antibodies: anti‐mouse MMP‐9 (dilution: 1:60; R&D Systems), anti‐mouse CD68 (macrophages, dilution: 1:400; ABD Serotec, Dusseldorf, Germany) and anti‐mouse Ly‐6B.2 (neutrophils, dilution: 1:50; ABD Serotec). Quantitative analysis was performed with MetaMorph software.…”
Apelin-13 treatment for 3 weeks did not alter the lesion size, but it significantly enhanced the stable phenotype of atherosclerotic plaques and improved serum lipid profile. These results indicate that activation of apelin system decreases plaque vulnerability.
Atherosclerosis is considered one of the primary causes of cardiovascular diseases (CVDs). Unpredictable rupture of the vulnerable atherosclerotic plaques triggers adverse cardiovascular events such as acute myocardial syndrome and even sudden cardiac death. Therefore, assessing the vulnerability of atherosclerotic plaques and early intervention are of significance in reducing CVD mortality. Nanomedicine possesses tremendous advantages in achieving the integration of the diagnosis and therapy of atherosclerotic plaques because of its magnetic, optical, thermal, and catalytic properties. Based on the pathological characteristics of vulnerable plaques, stimuli‐responsive nanoplatforms and surface‐functionalized nanoagents are designed and have drawn great attention for accomplishing the precise imaging and treatment of vulnerable atherosclerotic plaques due to their superior properties, such as high bioavailability, lesion‐targeting specificity, on‐demand cargo release, and low off‐target damage. Here, the characteristics of vulnerable plaques are generalized, and some targeted strategies for boosting the accuracy of plaque vulnerability evaluation by imaging and the efficacy of plaque stabilization therapy (including antioxidant therapy, macrophage depletion therapy, regulation of lipid metabolism therapy, anti‐inflammation therapy, etc.) are systematically summarized. In addition, existing challenges and prospects in this field are discussed, and it is believed to provide new thinking for the diagnosis and treatment of CVDs in the near future.
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