Search

Aims: Chemoattractants and their cognate receptors are essential for leucocyte recruitment during atherogenesis, and atherosclerotic plaques preferentially occur at predilection sites of the arterial wall with disturbed flow (d-flow). In profiling the endothelial expression of atypical chemoattractant receptors (ACKRs), we found that Ackr5 (CCRL2) was up-regulated in an endothelial subpopulation by atherosclerotic stimulation. We therefore investigated the role of CCRL2 and its ligand chemerin in atherosclerosis and the underlying mechanism., Methods and Results: By analysing scRNA-seq data of the left carotid artery under d-flow and scRNA-seq datasets GSE131776 of ApoE-/- mice from the Gene Expression Omnibus database, we found that CCRL2 was up-regulated in one subpopulation of endothelial cells in response to d-flow stimulation and atherosclerosis. Using CCRL2-/-ApoE-/- mice, we showed that CCRL2 deficiency protected against plaque formation primarily in the d-flow areas of the aortic arch in ApoE-/- mice fed high-fat diet. Disturbed flow induced the expression of vascular endothelial CCRL2, recruiting chemerin, which caused leucocyte adhesion to the endothelium. Surprisingly, instead of binding to monocytic CMKLR1, chemerin was found to activate β2 integrin, enhancing ERK1/2 phosphorylation and monocyte adhesion. Moreover, chemerin was found to have protein disulfide isomerase-like enzymatic activity, which was responsible for the interaction of chemerin with β2 integrin, as identified by a Di-E-GSSG assay and a proximity ligation assay. For clinical relevance, relatively high serum levels of chemerin were found in patients with acute atherothrombotic stroke compared to healthy individuals., Conclusions: Our findings indicate that d-flow-induced CCRL2 promotes atherosclerotic plaque formation via a novel CCRL2-chemerin-β2 integrin axis, providing potential targets for the prevention or therapeutic intervention of atherosclerosis., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Semaphorin 7A (Sema7A), a neural guidance cue, was recently identified to regulate atherosclerosis in mice. However, the clinical relevance of Sema7A with atherosclerotic diseases remains unknown. The aim of this study was to investigate the association between serum Sema7A and the risk of acute atherothrombotic stroke (AAS). We measured serum concentrations of Sema7A in 105 newly onset AAS cases and 105 age- and sex-matched controls, showing that median Sema7A level in AAS cases was over three times of that in controls (5.86 vs 1.66 ng/mL). Adjusted for hypertension, body mass index, fasting blood glucose, total cholesterol, triglyceride, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, current smoking and alcohol consumption, multivariate logistic regression showed that higher Sema7A was independently associated with the odds of AAS (OR = 6.40, 95% CI: 2.88-14.25). Each 1-standard deviation increase in Sema7A was associated with a threefold higher odds of AAS (OR = 3.42, 95% CI: 1.84-6.35). Importantly, adding Sema7A to a multivariate logistic model containing conventional cardiovascular risk factors improved the area under receiver operating characteristic curves from 0.831 to 0.891 for the association with AAS. In conclusion, elevated serum Sema7A is independently associated with the risk of AAS, suggesting that it may play a potential role in AAS., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: T2-weighted (T2w) intracranial vessel wall imaging (IVWI) provides good contrast to differentiate intracranial vasculopathies and discriminate various important plaque components. However, the strong cerebrospinal fluid (CSF) signal in T2w images interferes with depicting the intracranial vessel wall. In this study, we propose a T2-prepared sequence for whole-brain IVWI at 3T with CSF suppression. Methods: A preparation module that combines T2 preparation and inversion recovery (T2IR) was used to suppress the CSF signal and was incorporated into the commercial three-dimensional (3D) turbo spin echo sequence-Sampling Perfection with Application optimized Contrast using different flip angle Evolution (SPACE). This new technique (hereafter called T2IR-SPACE) was evaluated on nine healthy volunteers and compared with two other commonly used 3D T2-weighted sequences: T2w-SPACE and FLAIR-SPACE (FLAIR: fluid-attenuated inversion recovery). The signal-to-noise ratios (SNRs) of the vessel wall (VW) and CSF and contrast-to-noise ratios (CNRs) between them were measured and compared among these three T2-weighted sequences. Subjective wall visualization of the three T2-weighted sequences was scored blindly and independently by two radiologists using a four-point scale followed by inter-rater reproducibility analysis. A pilot study of four stroke patients was performed to preliminarily evaluate the diagnostic value of this new sequence, which was compared with two conventional T2-weighted sequences. Results: T2IR-SPACE had the highest CNR (11.01 ± 6.75) compared with FLAIR-SPACE (4.49 ± 3.15; p < 0.001) and T2w-SPACE (−56.16 ± 18.58; p < 0.001). The subjective wall visualization score of T2IR-SPACE was higher than those of FLAIR-SPACE and T2w-SPACE (T2IR-SPACE: 2.35 ± 0.59; FLAIR-SPACE: 0.52 ± 0.54; T2w-SPACE: 1.67 ± 0.58); the two radiologists' scores showed excellent agreement (ICC = 0.883). Conclusion: The T2IR preparation module markedly suppressed the CSF signal without much SNR loss of the other tissues (i.e., vessel wall, white matter, and gray matter) compared with the IR pulse. Our results suggest that T2IR-SPACE is a potential alternative T2-weighted sequence for assessing intracranial vascular diseases. [ABSTRACT FROM AUTHOR]

Background: Intracranial arterial calcification (IAC) is highly prevalent in ischemic stroke patients. However, data on the association of IAC with stroke recurrence and mortality remains limited. We examined the effect of IAC on the long-term recurrence of stroke and the risk of post-stroke mortality. Methods: Using a prospective stroke registry, we recruited 694 patients (mean age 71.6 ± 12.4; male sex 50.3%) since December 2004. IAC was visualized using the computed tomography exam that was made at hospital admission and was quantified with the Agatston method. All patients were regularly followed up till July 2016. The impacts of IAC on stroke recurrence and mortality were assessed using Cox-regression models with adjustments for age, sex, and relevant cardiovascular risk factors. Results: During a median follow-up period of 8.8 years, 156 patients (22.5%) suffered a recurrent stroke and 84 died (12.1%). We found that a higher IAC Agatston score related to a higher risk of stroke recurrence (HR per 1-SD increase in IAC: 1.30; 95% CI, 1.08–1.56, p = 0.005) and a higher risk of post-stroke mortality (HR per 1-SD increase, 1.44; 95% CI, 1.06–1.96, p = 0.019). After investigating etiology-specific risks of stroke-recurrence, we found that a higher IAC Agatston score specifically associated with small-vessel occlusive stroke. Conclusions: IAC is a strong risk factor for recurrent stroke and post-stroke mortality. Among stroke subtypes, IAC relates to higher risk of stroke recurrence among patients with small-vessel disease, which indicates chronic calcification detected in large cerebral arteries may have potential effects on the cerebrovascular beds extending to small vessels. [ABSTRACT FROM AUTHOR]

Emerging evidence shows that perivascular adipose tissue (PVAT) is crucially involved in inflammation and cardiovascular diseases. However, controversial results have been reported regarding the effect of PVAT in atherosclerosis. This study aimed to determine the role of PVAT in disturbed blood flow (d-flow)-induced carotid plaque formation. ApoE −/− male mice underwent partial carotid ligation (PCL) to induce d-flow in the left carotid artery (LCA) and were fed a high-fat diet for 2 weeks. Oil Red O and hematoxylin and eosin stains were used to determine adipose tissue. Thoracic PVAT from ApoE −/− or wild-type female mice were transplanted to the LCA of PCL-treated ApoE −/− mice. Carotid arteries were stained with Sudan IV to detect atherosclerotic lesions. Quantitative real-time reverse transcription polymerase chain reaction and immunofluorescence staining were performed to assess macrophage infiltration. By 2 weeks of the high-fat diet after PCL surgery, de novo adipose tissue was formed around the ligated LCA, where atherosclerotic plaques were also observed. Quantitative real-time reverse transcription polymerase chain reaction analysis of the newly formed PVAT revealed a similar transcription profile to native PVAT. Treatment with bisphenol A diglycidyl ether, a peroxisome proliferator-activated receptor γ inhibitor, diminished PVAT formation but increased plaque size and macrophage infiltration. Transplantation of thoracic PVAT from wild-type mice (PVAT-T WT ) rather than from ApoE −/− mice (PVAT-T ApoE−/− ) nearly abrogated LCA plaque macrophage content without affecting plaque size. Mechanistically, PVAT-T ApoE−/− showed higher messenger RNA levels of inflammatory cytokines compared with PVAT-T WT . Our findings suggest that regulated PVAT formation may confer protection against atherosclerosis-prone shear stress, probably through attenuation of focal inflammation. Clinical studies demonstrated that perivascular adipose tissue (PVAT) is anatomically close to atherosclerotic plaques and associated with plaque burden and vascular calcification. Here we showed a beneficial role of PVAT in atherosclerosis protection, suggesting the potential value of PVAT transplantation in disease control and prevention. [ABSTRACT FROM AUTHOR]