Role In Atherosclerotic Plaque Progression Research Articles

CircRNA-miRNA-mRNA network targets ubiquitin-mediated proteolysis pathway in coronary artery disease

The convoluted crosstalk of non-coding RNA (ncRNA) and mRNA results in the regulation of pathogenic processes in coronary artery disease (CAD). We utilized an in silico approach to assess circular RNA (circRNA), microRNA (miRNA), and mRNA, as potential biomarkers for CAD. CircRNA pertaining to CAD, atherosclerosis, and myocardial infarction were extracted from two databases namely Circad and circR2Disease. miRNA target sites & RNA-binding protein interactions were predicted using the circRNAinteractome database. miRNA gene targets were predicted using TargetScan, DIANA, and miRDIP. Gene enrichment analysis revealed that circRNA-miRNA distinctively targets ubiquitin-mediated proteolysis pathways (p = 0.02). Dysregulated ubiquitin pathway is known to play a role in atherosclerotic plaque progression and instability.

Cholesterol lowering activity of homoeopathic preparations of Colchicum autumnale – An in vitro study

Background: Total cholesterol content of erythrocyte membranes plays a critical role in atherosclerotic plaque progression and instability. Several homoeopathic medicines are known to have a significant role in the control of hyperlipidaemia. Colchicum autumnale is a plant remedy used mainly for gout, but also for hyperlipidaemia. Objectives: This is a study to assess the in vitro anti-cholesterol action of the Colchicum autumnale (Colch. at.) on the erythrocyte membrane. Materials and Methods: The study was conducted using a hyperlipidaemic blood sample which was divided into eight parts. Six different potencies of Colch. at. were tested, and two controls, one negative and another positive were used. Cholesterol was estimated using Liberman Burchard reagent and spectrophotometry. Results: In a hyperlipidemic blood sample, the range of reduction of cholesterol concentration was from 18.20% to 19.16%. The 6C potency removed 18.24% of cholesterol,12C potency removed 18.50% cholesterol,30C potency removed 19.02% cholesterol,200C potency removed 19.68% cholesterol and 10M potency removed 19.16% cholesterol. The maximum effect was seen in 1M potency where the reduction was 19.68 %. Conclusion: This study suggests that the Colchicum autumnale might be useful for the management of hypercholesterolemia.

Neutrophil membrane camouflaged nanoprobes for NIR-II fluorescence imaging of inflamed, high-risk atherosclerotic plaques in mouse and rabbit models

Atherosclerosis is the leading cause of vascular death worldwide, and inflammation plays a crucial role in atherosclerotic plaque progression and rupture. Fluorescent nanoprobes that can detect inflamed, high-risk atherosclerotic plaques and evaluate the therapeutic efficacy at the animal level in vivo are particularly meaningful. Herein, we developed a kind of neutrophil membrane-camouflaged nanoprobe in the second near-infrared spectral region (NIR-II) for the imaging of inflamed, high-risk atherosclerotic plaques in both mouse and rabbit models. Compared with free indocyanine green (ICG), the NIR-II fluorescence intensity of neutrophil biomimetic nanoparticles (Neu-NPs) was increased by 276% and had good stability in serum. Neu-NPs could specifically target inflamed, high-risk atherosclerotic plaques through the interaction of the chemokine receptor LFA-1with ICAM-1, which are highly expressed in inflamed sites. In the ApoE−/− mouse model, the signal-to background (S/B) ratio of the Neu-NP-treated mice was 1.67-fold higher than that of NP-treated mice. Even in large animals, such as the New Zealand white rabbit atherosclerosis model, Neu-NPs exhibited excellent targeting to high-risk atherosclerotic plaques. Moreover, the Neu-NPs could be used to reflect the reduction in plaque inflammation after the treatment and could thus be used for therapeutic evaluation and drug screening. Therefore, this highly biocompatible neutrophil membrane-camouflaged nanoprobe may be a new nanocarrier for the treatment of chronic inflammatory diseases such as atherosclerosis. Moreover, the use of NIR-II fluorescence imaging in mice and rabbits with atherosclerosis extends the scope of this emerging imaging technology.

Fractional Flow Reserve and Instantaneous Wave-Free Ratio Predict Pathological Wall Shear Stress in Coronary Arteries: Implications for Understanding the Pathophysiological Impact of Functionally Significant Coronary Stenoses.

BackgroundThe pathophysiological mechanism behind adverse outcomes associated with ischemia‐inducing epicardial coronary stenoses and microcirculatory dysfunction remains unclear. Wall shear stress (WSS) plays an important role in atherosclerotic plaque progression and vulnerability. We aimed to evaluate the relationship between WSS, functionally significant epicardial coronary stenoses, and microcirculatory dysfunction.Methods and ResultsPatients undergoing invasive coronary physiology testing were included. Fractional flow reserve, instantaneous wave‐free ratio, and the index of microcirculatory resistance were measured. Quantitative coronary angiography was used to obtain the lesion percentage diameter stenosis. Computational fluid dynamics analysis was performed to calculate WSS parameters. Multiple regression analysis was performed to calculate the standardized regression coefficient (β) for the coronary physiology indices.A total of 107 vessels from 88 patients were included. Fractional flow reserve independently predicted the total area of low WSS (β=−0.44; 95% CI, −0.62 to −0.25; P<0.001) and maximum lesion WSS (β=−0.53; 95% CI, −0.70 to −0.36; P<0.001) after adjusting for percentage diameter stenosis and index of microcirculatory resistance. Similarly, instantaneous wave‐free ratio also independently predicted the total area of low WSS (β=−0.45; 95% CI, −0.62 to −0.28; P<0.001) and maximum lesion WSS (β=−0.58; 95% CI, −0.73 to −0.43; P<0.001). The index of microcirculatory resistance did not predict either low or high WSS.ConclusionsFractional flow reserve and instantaneous wave‐free ratio independently predicted the total burden of low WSS and maximum lesion WSS in coronary arteries. No relationship was found between microcirculatory dysfunction and WSS.

EV-associated cytokines in human atherosclerotic plaques cultured ex vivo

Background and Aims: Extracellular vesicles (EVs) have been shown to play a role in atherosclerotic plaque progression. However, the mechanisms of this process are poorly understood, partially, due to the absence of ex vivo models that faithfully reproduce the plaque’s structure and microenvironment. Using this model, we studied the distribution of cytokines between EV-associated and soluble fractions in the culture medium of our model of human atherosclerotic plaque culture that allows the investigation of intracellular interactions.

Calcium-Binding Protein S100A4 Is Upregulated in Carotid Atherosclerotic Plaques and Contributes to Expansive Remodeling.

BackgroundCarotid plaques with expansive arterial remodeling are closely related to cerebral ischemic events. Although S100A4 (S100 calcium‐binding protein A4) is expressed in atherosclerotic lesions, its role in atherosclerotic plaque progression remains unknown. In this study, we examined the association between carotid arterial expansive remodeling and S100A4 expression.Methods and ResultsPreoperative high‐resolution magnetic resonance imaging was used to assess luminal stenosis and vascular remodeling in patients undergoing carotid endarterectomy. To examine murine carotid atherosclerosis, we induced experimental lesions by flow cessation in apolipoprotein E‐deficient mice fed a high‐fat diet. The role of S100A4 in plaque formation and smooth muscle cell proliferation was investigated in vivo and in vitro, respectively. Human carotid arterial expansive remodeling showed positive correlations with the expression of S100A4, MMP2, and MMP9. S100A4 mRNA levels were positively correlated with those of MMP2, MMP9, and MMP13. S100A4 was expressed in vascular smooth muscle cells (VSMCs) and VSMC‐derived foam cells in the plaque shoulder and marginal areas. S100A4 expression increased concomitantly with plaque formation in our animal model. Exogenous recombinant S100A4 protein enhanced the levels of Mmp2, Mmp9, and Mmp13 and the cell proliferation ability in VSMCs. A chemotaxis assay indicated that extracellular S100A4 functions as a chemoattractant for VSMCs.ConclusionsS100A4 expression was elevated in human carotid plaques and showed a positive correlation with the degree of expansive remodeling. S100A4‐positive VSMC‐derived cells are considered to play an important role in carotid expansive remodeling.

Effects of Increased Arterial Stiffness on Atherosclerotic Plaque Amounts.

Increased arterial stiffness is associated with atherosclerosis in humans, but there have been limited animal studies investigating the relationship between these factors. We bred elastin wildtype (Eln+/+) and heterozygous (Eln+/-) mice to apolipoprotein E wildtype (Apoe+/+) and knockout (Apoe-/-) mice and fed them normal diet (ND) or Western diet (WD) for 12 weeks. Eln+/- mice have increased arterial stiffness. Apoe-/- mice develop atherosclerosis on ND that is accelerated by WD. It has been reported that Apoe-/- mice have increased arterial stiffness and that the increased stiffness may play a role in atherosclerotic plaque progression. We found that Eln+/+Apoe-/- arterial stiffness is similar to Eln+/+Apoe+/+ mice at physiologic pressures, suggesting that changes in stiffness do not play a role in atherosclerotic plaque progression in Apoe-/- mice. We found that Eln+/-Apoe-/- mice have increased structural arterial stiffness compared to Eln+/+Apoe-/- mice, but they only have increased amounts of ascending aortic plaque on ND, not WD. The results suggest a change in atherosclerosis progression but not end stage disease in Eln+/-Apoe-/- mice due to increased arterial stiffness. Possible contributing factors include increased blood pressure and changes in circulating levels of interleukin-6 (IL6) and transforming growth factor beta 1 (TGF-β1) that are also associated with Eln+/- genotype.

Role of KCa3.1 Channels in Macrophage Polarization and Its Relevance in Atherosclerotic Plaque Instability.

Emerging evidence indicates that proinflammatory macrophage polarization imbalance plays a key role in atherosclerotic plaque progression and instability. The calcium-activated potassium channel KCa3.1 is critically involved in macrophage activation and function. However, the role of KCa3.1 in macrophage polarization is unknown. This study investigates the potential role of KCa3.1 in transcriptional regulation in macrophage polarization and its relationship to plaque instability. Human monocytes were differentiated into macrophages using macrophage colony-stimulating factor. Macrophages were then polarized into proinflammatory M1 cells by interferon-γ and lipopolysaccharide and into alternative M2 macrophages by interleukin-4. A model for plaque instability was induced by combined partial ligation of the left renal artery and left common carotid artery in apolipoprotein E knockout mice. Significant upregulation of KCa3.1 expression was observed during the differentiation of human monocytes into macrophages. Blocking KCa3.1 significantly reduced the expression of proinflammatory genes during macrophages polarization. Further mechanistic studies indicated that blocking KCa3.1 inhibited macrophage differentiation toward the M1 phenotype by downregulating signal transducer and activator of transcription-1 phosphorylation. In animal models, KCa3.1 blockade therapy strikingly reduced the incidence of plaque rupture and luminal thrombus in carotid arteries, decreased the expression of markers associated with M1 macrophage polarization, and enhanced the expression of M2 markers within atherosclerotic lesions. These results suggest that blocking KCa3.1 suppresses plaque instability in advanced stages of atherosclerosis by inhibiting macrophage polarization toward an M1 phenotype.

Using 2D in Vivo Ivus-based Models for Human Coronary Plaque Progression Analysis and Comparison with 3d Fsi Models

It is believed that mechanical stress plays an important role in atherosclerotic plaque progression and rupture process. However, 3D model construction is very time consuming and not practical for clinical implementation. This paper is investigating if 2D models could be used to replace 3D models to perform correlation analysis and achieve similar results. Patient follow-up in vivo intravascular ultrasound coronary plaque data were acquired to construct 2D structure-only and 3D FSI models to obtain plaque wall stress (PWS) and strain (PWSn) data and investigate correlations between plaque progression measured by wall thickness increase(WTI) and three risk factors: wall thickness (WT), PWS and PWSn. Our results indicated that while stress/strain differences between 2D and 3D models were about 30%, correlation results from 2D models were in general consistent with those obtained from 3D models.

Increased platelet reactivity is associated with circulating platelet-monocyte complexes and macrophages in human atherosclerotic plaques.

ObjectivePlatelet reactivity, platelet binding to monocytes and monocyte infiltration play a detrimental role in atherosclerotic plaque progression. We investigated whether platelet reactivity was associated with levels of circulating platelet-monocyte complexes (PMCs) and macrophages in human atherosclerotic carotid plaques.MethodsPlatelet reactivity was determined by measuring platelet P-selectin expression after platelet stimulation with increasing concentrations of adenosine diphosphate (ADP), in two independent cohorts: the Circulating Cells cohort (n = 244) and the Athero-Express cohort (n = 91). Levels of PMCs were assessed by flow cytometry in blood samples of patients who were scheduled for percutaneous coronary intervention (Circulating Cells cohort). Monocyte infiltration was semi-quantitatively determined by histological examination of atherosclerotic carotid plaques collected during carotid endarterectomy (Athero-Express cohort).ResultsWe found increased platelet reactivity in patients with high PMCs as compared to patients with low PMCs (median (interquartile range): 4153 (1585–11267) area under the curve (AUC) vs. 9633 (3580–21565) AUC, P<0.001). Also, we observed increased platelet reactivity in patients with high macrophage levels in atherosclerotic plaques as compared to patients with low macrophage levels in atherosclerotic plaques (mean±SD; 8969±3485 AUC vs. 7020±3442 AUC, P = 0.02). All associations remained significant after adjustment for age, sex and use of drugs against platelet activation.ConclusionPlatelet reactivity towards ADP is associated with levels of PMCs and macrophages in human atherosclerotic carotid plaques.

Intravascular blood sampling using the Thrombuster II catheter does not cause artifactual platelet activation

Platelets and leukocytes play an important role in atherosclerotic plaque progression. Determining the activation state of both the platelet and leukocyte population at the lesion site has become increasingly of interest. A novel thrombus aspiration catheter, the Thrombuster II (Kaneka Medical Products, Osaka, Japan), has recently been introduced into clinical practice, and is finding rapidly increasing use. This catheter is capable of local blood collection within the coronary tree, but to our knowledge has not previously been validated to demonstrate lack of platelet activation. This study therefore aims to establish whether or not blood sampling via the Thrombuster II results in artefactual platelet activation. Duplicate blood samples were obtained from the descending aorta using both the Thrombuster II and a femoral arterial sheath (control). The samples were collected into CTAD (to minimize ex vivo activation) blood collection tubes and processed for flow cytometry analysis. Platelet activation was assessed based on the expression of CD62P, PAC-1 binding and platelet CD147 expression. Platelet-leukocyte aggregates were also examined. No significant difference was noted between the sheath samples and the Thrombuster II catheter. The Thrombuster II catheter is a novel thrombus aspiration device capable of providing the assessment of platelet activation and platelet-leukocyte aggregates in coronary arteries.

Black-blood dynamic contrast-enhanced carotid artery wall MRI with SRDIR preparation

Background Inflammation plays a major role in atherosclerotic plaque progression and disruption [1]. Dynamic gadolinium contrast-enhanced (DCE) vessel wall imaging has been used to compute a set of contrast kinetic parameters that may characterize the extent of inflammation of carotid plaques [2-4]. However, previous DCE techniques are limited to a 2D bright-blood acquisition and thus the accuracy of wall signal assessment could be compromised. This work aimed to develop a 3D black-blood DCE technique.

Transcriptome Analysis in Patients with Progressive Coronary Artery Disease: Identification of Differential Gene Expression in Peripheral Blood

Inflammation as a systemic process plays a central role in atherosclerotic plaque progression (PP). Here we investigated other systemic correlates of PP by global gene expression profiling (GEP) in peripheral blood. From a database of 45,727 coronary angiograms, we identified two patient groups with good risk factor control, but different clinical evolution: First, 16 patients had significant PP leading to repeated coronary interventions, and second, 16 patients had angiographically documented stable courses. GEP revealed 93 differentially expressed genes, of which 23 have unknown function. Among the remaining 70 genes, 10 were associated with progenitor and pluripotent cells, but only three genes with atherosclerosis. We developed a risk prediction gene signature by a multivariable statistical model integrating comprehensive laboratory and clinical patient data. This signature identified PP with high sensitivity and specificity for new patients, as estimated by resampling techniques. GEP results were validated by qPCR for ANK2 and GSTT1.

Total cholesterol content of erythrocyte membranes is associated with the severity of coronary artery disease and the therapeutic effect of rosuvastatin

Introduction. Numerous studies suggest that total cholesterol content of erythrocyte membranes (CEM) might play a critical role in atherosclerotic plaque progression and instability. However, the exact role of CEM in atherosclerosis remains obscure. Our study was designed to investigate the association between CEM and the severity of coronary artery disease (CAD), and to assess the effect of rosuvastatin on CEM levels.Methods. CEM levels were assessed in 136 participants, including acute coronary syndrome (ACS) (non-ST-segment elevation ACS (NSTEACS) and ST-segment elevation myocardial infarction (STEMI)), stable angina pectoris (SAP), and controls. The Gensini score was used to estimate the severity of CAD. Additionally, 54 patients with CAD were medicated with rosuvastatin, 5 or 10 mg once daily, and then checked at 6 months.Results. The highest level of CEM was found in the STEMI group, followed by the NSTEACS, the SAP, and the control groups. Gensini score in group IV (CEM > 141.6 μg/mg) was markedly higher compared with group I (CEM ≤77.6 μg/mg). Gensini scores in group II (77.6 < CEM ≤111.1 μg/mg) and group III (111.1 < CEM ≤141.6 μg/mg) were also higher than in group I (all P < 0.001). Furthermore, a positive correlation was found between CEM levels and Gensini score (r = 0.714, P < 0.001). CEM levels were dose-dependently reduced by rosuvastatin therapy.Conclusions. CEM levels are positively associated with the severity of CAD, meaning that CEM might contribute to the development of CAD. Importantly, rosuvastatin could decrease CEM levels in patients with CAD and might effectively help to attenuate the progression of CAD.

Artemisinin inhibits extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase‐9 expression via a protein kinase Cδ/p38/extracellular signal‐regulated kinase pathway in phorbol myristate acetate‐induced THP‐1 macrophages

1. Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinases (MMPs) by monocytes/macrophages has been proposed to play a significant role in atherosclerotic plaque progression and rupture. The aim of the present study was to explore whether artemisinin, a natural extract from Artemisia annua, could decrease EMMPRIN and MMP-9 expression in phorbol myristate acetate (PMA)-induced macrophages by regulating the protein kinase (PK) Cδ/c-Jun N-terminal kinase (JNK)/p38/extracellular signal-regulated kinase (ERK) pathway. 2. Human monocytic THP-1 cells were pretreated with 20-80 μg/mL artemisinin for 4 h or 1-10 μmol/L rottlerin for 1 h prior to stimulation with PMA (100 nmol/L) for another 48 h. Cells were collected to analyse the induction of EMMPRIN and MMP-9. Upstream pathway analysis using the PKCδ inhibitor rottlerin detected activation of the PKCδ/JNK/p38/ERK pathway. 3. Artemisinin (20-80 μg/mL) significantly inhibited the induction of EMMPRIN and MMP-9 at both the transcriptional and translational levels in a dose-dependent manner in PMA-induced macrophages. In addition, artemisinin (20-80 μg/mL) strongly blocked PKCδ/JNK/p38/ERK MAPK phosphorylation. The PKCδ inhibitor rottlerin (1-10 μmol/L) also significantly inhibited JNK/p38/ERK phosphorylation and decreased EMMPRIN and MMP-9 mRNA and protein expression. 4. The results of the present study suggest that artemisinin inhibits EMMPRIN and MMP-9 expression and activity by suppressing the PKCδ/ERK/p38 cascade in PMA-induced macrophages.

Targeted Iron Oxide Particles for In Vivo Magnetic Resonance Detection of Atherosclerotic Lesions With Antibodies Directed to Oxidation-Specific Epitopes

The aim of this study was to determine whether iron oxide particles targeted to oxidation-specific epitopes image atherosclerotic lesions. Oxidized low-density lipoprotein plays a major role in atherosclerotic plaque progression and destabilization. Prior studies indicate that gadolinium micelles labeled with oxidation-specific antibodies allow for in vivo detection of vulnerable plaques with magnetic resonance imaging (MRI). However, issues related to biotransformation/retention of gadolinium might limit clinical translation. Iron oxides are recognized as safe and effective contrast agents for MRI. Because the efficacy of passively targeted iron particles remains variable, it was hypothesized that iron particles targeted to oxidation-specific epitopes might increase the utility of this platform. Lipid-coated ultra-small superparamagnetic iron particles (LUSPIOs) (<20 nm) and superparamagnetic iron particles (<40 nm) were conjugated with antibodies targeted to either malondialdehyde-lysine or oxidized phospholipid epitopes. All formulations were characterized, and their in vivo efficacy evaluated in apolipoprotein E deficient mice 24 h after bolus administration of a 3.9-mg Fe/kg dose with MRI. In vivo imaging data were correlated with the presence of oxidation-specific epitopes with immunohistochemistry. MRI of atherosclerotic lesions, as manifested by signal loss, was observed after administration of targeted LUSPIOs. Immunohistochemistry confirmed the presence of malondialdehyde-epitopes and iron particles. Limited signal attenuation was observed for untargeted LUSPIOs. Additionally, no significant arterial wall uptake was observed for targeted or untargeted lipid-coated superparamagnetic iron oxide particles, due to their limited ability to penetrate the vessel wall. This study demonstrates that LUSPIOs targeted to oxidation-specific epitopes image atherosclerotic lesions and suggests a clinically translatable platform for the detection of atherosclerotic plaque.

Effect of Statin on the Reference Segments after Bare-Metal Stent Implantation

Effect of Statin on the Reference Segments after Bare-Metal Stent Implantation

Increased Neovascularization in Advanced Lipid-Rich Atherosclerotic Lesions Detected by Gadofluorine-M-Enhanced MRI

Background— Inflammation and neovascularization may play a significant role in atherosclerotic plaque progression and rupture. We evaluated gadofluorine-M-enhanced MRI for detection of plaque inflammation and neovascularization in an animal model of atherosclerosis. Methods and Results— Sixteen rabbits with aortic plaque and 6 normal control rabbits underwent gadofluorine-M-enhanced MRI. Eight rabbits had advanced atherosclerotic lesions, whereas the remaining 8 had early lesions. Magnetic resonance atherosclerotic plaque enhancement was meticulously compared with plaque inflammation and neovessel density as assessed by histopathology. Advanced plaques and early atheroma were enhanced after gadofluorine-M injection. Control animals displayed no enhancement. After accounting for the within-animal correlation of observations, mean contrast-to-noise ratio was significantly higher in advanced plaques than compared with early atheroma (4.29�0.21 versus 3.00�0.32; P =0.004). Macrophage density was higher in advanced plaques in comparison to early atheroma (geometric mean=0.50 [95% CI, 0.19 to 1.03] versus 0.25 [0.07 to 0.42]; P =0.05). Furthermore, higher neovessel density was observed in advanced plaques (1.83 [95% CI, 1.51 to 2.21] versus 1.29 [0.99 to 1.69]; P =0.05). The plaque accumulation of gadofluorine-M correlated with increased neovessel density as shown by linear regression analysis ( r =0.67; P &lt;0.001). Confocal and fluorescence microscopy revealed colocalization of gadofluorine-M with plaque areas containing a high density of neovessels. Conclusion— Gadofluorine-M-enhanced MRI is effective for in vivo detection of atherosclerotic plaque inflammation and neovascularization in an animal model of atherosclerosis. These findings suggest that gadofluorine-M enhancement reflects the presence of high-risk plaque features believed to be associated with plaque rupture. Gadofluorine-M plaque enhancement may therefore provide functional assessment of atherosclerotic plaque in vivo.

Choking off Plaque Neovascularity

“For every complex problem there is a simple solution—and it’s wrong.” — H.L. Mencken Atherosclerosis is a highly prevalent disease that results from a complex interplay between lipids, endothelial cells, immunoinflammatory cells, cytokines, extracellular matrix, and neovascularization.1 Several lines of evidence suggest that increased adventitial and plaque neovascularity, commonly observed in murine and human atherosclerosis, plays an important role in progression and, possibly, destabilization of atherosclerosis.1–9 Increased plaque neovascularity may contribute to plaque progression by its link to inflammation, as a source of intraplaque hemorrhage and plaque lipid (Figure).1,5,7–9 Schematic illustrates the potential mechanisms of plaque neoangiogenesis and its potential role in atherosclerotic plaque progression. The putative mechanism by which oral DNA Vaccine against Flk-1 (fetal liver kinase or VEGFR2)-expressing cells may inhibits angiogenesis and plaque progression is also shown. The red arrows indicate the potential adverse aspects of such a therapeutic strategy. VEGF indicates vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor 2; IL-8, interleukin-8. See page 1095 The precise mechanisms contributing to increased plaque neovascularity remain to be defined; however, inflammation and one or more angiogenic growth factors have been implicated. One of the pathways for angiogenesis leading to neovascularization involves the family of vascular endothelial growth factor(s) (VEGF) and their receptors (VEGFR). Therefore, VEGF and VEGFR mediated angiogenesis has emerged …