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Abstract The authors present a short review of the personality, clinical and scientific contributions of a distinguished member of our Academy, the Artery Society and so many others, where he contributed landmark advances in many fields of arterial function and cardiovascular risk. The Editorial Board of the Artery Research Journal and the Executive Committee of the Artery Society present their due respects to Prof. Michel Safar.

The authors present a short review of the personality, clinical and scientific contributions of a distinguished member of our Academy, the Artery Society and so many others, where he contributed landmark advances in many fields of arterial function and cardiovascular risk. The Editorial Board of the Artery Research Journal and the Executive Committee of the Artery Society present their due respects to Prof. Michel Safar. [ABSTRACT FROM AUTHOR]

IntroductionAmine oxidase copper containing 3 (AOC3) displays adhesion between leukocytes and endothelial cells and enzymatic functions. Given its controversial role in atherogenesis, we proposed to investigate the involvement of AOC3 in the formation of atherosclerotic plaques in ApoE−/−AOC3−/− mice and human coronary arteries.MethodsLesions, contractile markers, and AOC3 were studied in aortic tissues from 15- and 25-week-old mice and different stages of human coronary atherosclerotic arteries by immunohistochemistry (IHC) and/or western blot. Human VSMCs, treated or not with LJP1586, an AOC3 inhibitor, were used to measure differentiation markers by qPCR. AOC3 co-localization with specific cell markers was studied by using confocal microscopy in mice and human samples.ResultsAt 15 weeks old, the absence of AOC3 was associated with increased lesion size, α-SMA, and CD3 staining in the plaque independently of a cholesterol modification. At 25 weeks old, advanced plaques were larger with equivalent staining for α-SMA while CD3 increased in the media from ApoE−/−AOC3−/− mice. At both ages, the macrophage content of the lesion was not modified. Contractile markers decreased whereas MCP-1 appeared augmented only in the 15-week-old ApoE−/−AOC3. AOC3 is mainly expressed by mice and human VSMC is slightly expressed by endothelium but not by macrophages.ConclusionAOC3 knock-out increased atherosclerotic plaques at an early stage related to a VSMC dedifferentiation associated with a higher T cells recruitment in plaques explained by the MCP-1 augmentation. This suggests that AOC3 may have an important role in atherosclerosis independent of its canonical inflammatory effect. The dual role of AOC3 impacts therapeutic strategies using pharmacological regulators of SSAO activity.

Aims Although the risk of thrombosis is well documented for inflammatory bowel disease [IBD] patients, the underlying pathological mechanism seems to be different from other thrombotic conditions. Determining the factors responsible for the increased risk of thrombosis in IBD would help to improve the management of this frequent complication. Methods We studied the interplay between platelets, coagulation, and von Willebrand factor [VWF] in 193 IBD patients and in experimental models [acute and chronic] of colitis in wild-type and VWF-deficient mice. Results We found a platelet-dependent increase in thrombin generation in IBD patients and in our mouse model of colitis. Agglutinated platelets were present in the blood of patients and mice. Interestingly, we observed not only a significant increase in total VWF antigen, but we were also able to detect the presence of active VWF [VWF in its platelet-binding conformation; 3.2 ± 2.7 μg/mL] in the plasma of 30% of all IBD patients. In healthy controls, active VWF levels were <0.3 μg/mL. This led us to further explore experimental colitis in VWF-deficient mice and we observed that these mice were protected against the procoagulant state triggered by the colitis. Unexpectedly, these mice also showed a significant worsening of colitis severity in both acute and chronic models. Conclusion Platelets and VWF [including its active form] appear to be central players in the procoagulant phenotype in IBD. We observed that the role of VWF in haemostasis differs from its role in colonic tissue healing, potentially opening new therapeutic avenues for a life-threatening complication in IBD patients. [ABSTRACT FROM AUTHOR]

Background: Pulse wave velocity (PWV) is a marker of arterial stiffness, which is intrinsically highly correlated with blood pressure (BP). However, the interplay of PWV and BP heritability has not been extensively studied. This study aimed to estimate the heritability of PWV and BP and determine the genetic correlation between PWV and BP. Methods: The heritability of PWV and BP was estimated in 1080 subjects from the STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) cohort with at least one relative using a linear mixed model within one frequentist and one Bayesian framework implemented, respectively, in the Gaston and MCMCglmm R packages. Then their genetic correlations were also estimated. Results: The heritability estimations for PWV were within the same range of the heritability of systolic BP and diastolic BP (23%, 19%, and 27%, respectively). Daytime heritability of BP was higher than nighttime BP. In addition, phenotypic correlations between PWV and systolic BP/diastolic BP were, respectively, 0.34 and 0.23, whereas nonsignificant genetic correlations were 0.08 and 0.22 respectively, indicating that PWV and diastolic BP shared more polygenic codeterminants than PWV and systolic BP. Conclusions: Our results suggest that the heritability of PWV is >20% and within the same range as BP heritability. It also suggests that the link between PWV and BP goes beyond phenotypic association: PWV and BP (in particular diastolic BP) share common genetic determinants. This genetic interdependence of PWV and BP appears largely polygenic. [ABSTRACT FROM AUTHOR]

Background: With aging and atherosclerosis plaque development, endothelial permeability increases leading to blood and platelets (PLT) infiltration into the vascular wall. In the media, vascular smoothmuscle cells (VSMCs) are crucial for clearance of infiltrated molecules and cells including senescent red blood cells (1). Moreover, blood has a high concentration of macromolecules making it a macromolecularly crowded environment (MMC). The objective is to decipher the clearance mechanisms of PLT by VSMCs and the influence of MMC on it. Methods: Human VSMCs were cultured with either human: (i) fresh PLT, (ii) ADP-activated PLT, (iii) senescent PLT. PLT and VSMCs were stained with fluorescent tracers prior their co-culture. We also cultured VSMC in media supplemented with crowders to mimic MMC. Results: After three or seven days of co-culture, we observed that activated and/or senescent PLT, which are characterized by phosphatidylserine exposure, were localized within VSMCs. In contrast to fresh red blood cells that are not phagocytosed by VSMCs, fresh PLT were also entrapped within VSMCs. We then stained VSMCs with phalloidin, an actin filament dye, revealing that PLT are surrounded by an actin shell within the VSMC. In addition, we observed that MMC modified the deposition of extracellular matrix (fibronectin, laminin and sugar moieties) by VSMCs. Conclusions: VSMCs engulf PLT with an actin-dependent endocytosis process and MMC modifies the secretory phenotype of VSMC. PLT engulfment could be an inducible pathogenic event that is responsible for VSMC phenotypic switching in atherosclerosis and their procoagulant status. [ABSTRACT FROM AUTHOR]

Introduction: Inflammatory bowel disease (IBD) represents an independent risk factor for thrombosis. However, the causes of this increased risk of thrombosis are still elusive. Objectives: We aim to decipher the main players in the procoagulant phenotype associated with IBD.Methods and Results: Coagulation phenotype assessment was performed in IBD patients included in the "I-BANK project" (CHRU Nancy), a prospective monocentric study recruiting 1000 IBD patients and in a mouse model of IBD (dextran sulphate sodium: DSS). We found an increase in platelet count in active IBD patients and an increased thrombin generation (TG) in platelet-rich plasma. Similar results were obtained in mice treated with DSS. In platelet-poor plasma, TG was not increased, highlighting the role of platelets in this phenotype. In addition, both mice and active patients showed platelet agglutination on blood smears. As circulating von Willebrand factor (VWF), which has a procoagulant function and may be involved in platelet agglutination, is elevated in IBD patients, we used VWF-deficient mice. In these mice, TG in platelet-rich plasma was not increased in response to DSS treatment. In contrast, VWF-deficient mice receiving DSS showed worsened colonic tissue damage, highlighting the importance of maintaining a normal coagulation balance in IBD. Conclusion: The procoagulant phenotype in IBD depends on platelet agglutination via VWF. Further studies are needed to assess the possible beneficial effect of VWF inhibition in IBD patients at high risk of thrombosis without aggravating tissue damage. [ABSTRACT FROM AUTHOR]

Background: Integrin av is a receptor for adhesion proteins expressed at high density in vascular smooth muscle cells (VSMC) whose phenotypic modulation plays a crucial role in arterial ageing. Objectives: To define the arterial phenotype in mice conditionally inactivated for the integrin av subunit in VSMC and the role of this integrin in angiotensin II (Ang II)-induced arterial and VSMC stiffness. Methods and Results: We used a VSMC specific knock-out αv mouse model induced in adult mice by injection of tamoxifen. Trangenic mice (αvSMKO) and control littermates (Ctrl) were infused with Ang II (1.5 mg/kg/day) for 4 weeks. The pressure effect of Ang II was similar in Ctrl and αvSMKO mice. The carotid distensibility/pressure and elastic modulus/wall stress curves were similar in control and αvSMKO mice, indicating comparable arterial stiffness. Ang II treatment resulted in increased carotid stiffness in both groups without changes in vascular reactivity and myogenic tone. Electronic microscopy revealed less vesicles containing fiber-like materials in the SMCs of Ang II-treated αvSMKO carotids Elastic modulus of cultured VSMCs determined using atomic force microscopy was higher after Ang II treatment in cells from both groups. At baseline and after treatment, elastic modulus was higher in cells from αvSMKO mice than in cells from Ctrl mice. Conclusion: Inactivation of αv-containing integrins on VSMCs increases cell stiffness. The general mechanism involves a cross-talk between extracellular matrix, αv integrins and cytoskeletal complex. The lack of distensibility changes suggests additional changes at the level of αv-mediated dynamics of focal adhesion. [ABSTRACT FROM AUTHOR]

Introduction: Aneurysms of the ascending (TAA) and the abdominal aorta (AAA) share the common feature of dilation of the aorta but differ by their respective physiopathology and tissue environment in human. AAA is characterized by associated thrombosis forming an intraluminal clot, whereas thrombotic events are extremely rare in TAA, suggesting different coagulant properties between AAA and TAA. Objectives: To compare coagulation capacities at tissue and cellular levels, derived from both AAA and TAA. Methods and Results: Human healthy aorta, AAA or TAA tissues and primary cultures of aortic smooth muscle cells (SMCs) were used. Thrombin generation was monitored by thrombography in the presence of healthy plasma. AAA tissues and SMCs have a higher ability to promote fibrin formation, to activate prothrombin, and to mobilize the tissue factor (TF) pathway, whereas TAA tissues and derived SMCs express an anti-thrombotic phenotype. Activation of the TF pathway in AAA tissue and SMCs is provoked by oxidative stress, protease-activated receptor 2 (PAR-2) overexpression and nuclear factor-kappa B (NF-κB) mobilization which could be reproduced by SMC efferocytosis of senescent red blood cells. Moreover, the high coherence between what was observed ex vivo in tissue and in passaged SMCs in vitro, demonstrated a procogulant phenotype shift in AAA SMCs, potentially as an imprinting of environmental pro-oxidative conditions of AAA. Conclusion: Our data indicate that oxidative stress-induced activation of the PAR-2 - NF-κB axis and leads to an increase in TF activity and prothrombotic properties of SMCs from AAA. [ABSTRACT FROM AUTHOR]

Background and Objectives: Glycocalyx, a thin layer of carbohydrates covering endothelial cells, is important for interactions between blood components and the vascular wall. It is implicated in circulating cells adhesion, inflammation, and coagulation regulation and can be damaged in some diseases. The prevailing hypothesis is that hypertension is the primary factor involved in glycocalyx degradation. However, our preliminary data challenge this view and point to a more important role of inflammation. The objective of this study was to assess the respective roles of inflammation and hemodynamic on the endothelial glycocalyx degradation. Methods and Results: Plasma concentrations of syndecan-1, a glycocalyx degradation marker, IL-6, IL-8, IL-10, ICAM-1 and VCAM-1 were quantified by ELISA in 327 participants (62 ± 14 years). Subjects were categorized as atherosclerotic cardio-vascular diseases (ASCVD) patients or controls and performed all a blood pressure and pulse wave velocity assessment. Syndecan-1 was positively associated with circulating IL-6 (p < 0.001), IL-8 (p = 0.002), and IL-10 concentrations (p = 0.006) and with adhesion molecules ICAM-1 and VCAM-1 (p < 001). No relation was observed between syndecan-1 and hemodynamic parameters, thus confirming the major role of inflammatory status in the degradation of endothelial glycocalyx. Interestingly, subjects with higher plasma concentration of syndecan-1 (third tertile) displayed more clinical manifestation of atherosclerosis (65 vs 42%; p < 0.001) than those with lower concentration (first tertile). Conclusions: Endothelial glycocalyx degradation is rather associated with inflammatory status than hemodynamic parameters. Higher degradation of glycocalyx is associated with increased percentage of ASCVD suggesting a direct relation between glycocalyx degradation and increased risk of atherosclerotic diseases. [ABSTRACT FROM AUTHOR]

Background: Ctip2/Bcl11b is a transcription factor with dual action (repression/activation) that couples epigenetic regulation to gene transcription in a variety of physiological responses under healthy and pathological conditions of various tissues. Single nucleotide polymorphisms of Ctip2/Bcl11b gene are associated with a higher susceptibility for aortic stiffness (1). although Ctip2/Bcl11b has been proposed as a crucial regulator of aortic smooth muscle function (2), its mechanism of action in smooth muscle cells is still to be uncovered. Methods: Morphological, cellular and molecular analysis were carried out on the arteries of smooth muscle cell-specific Ctip2-knockout (KO) mice at 3, 7, 28 days after tamoxifen injections. Results: There is no difference between control and mutant mice at the macroscopic level 3 days after Ctip2 KO induction, however, 7 day after Bcl11b inactivation, 65% of the Ctip2-SMKO mice showed signs of hemorrhage in the distal part of the thoracic aorta near the abdominal aorta. The histological examination of thoracic aorta at 7 indicated the presence of "bumpy region" in the mutant aorta. These areas is covered by a thicker layer of extracellular matrix and the presence of IgG positive cells, indicating that cell death is occurring. However, the hemorrhages is contained over time, do not impact mice survival. qPCR analysis indicated the altered expression of circadian-related genes such as genes of Bmal and ciart. Conclusions: Our data indicate the primary effect of Bcl11b inactivation on cell death, probably by necroptosis. [ABSTRACT FROM AUTHOR]

Arterial stiffening is a strong independent risk factor for cardiovascular disease. B-cell leukaemia 11b (BCL11B) is a transcription factor known as an essential regulator in T lymphocytes differentiation and neuronal development. Several genome-wide association studies showed that single nucleotide polymorphisms (SNPs) in the 3'gene desert of Bcl11b are associated with a higher susceptibility for aortic stiffness and blood pressure control. However, its role in smooth muscle cells and mechanism of action remains to be uncovered. Our aims are: (1) to analyse the role of Bcl11b in vascular system; (2) to characterize the signalling pathways related to Bcl11b in cell death. Morphological, cellular and molecular analysis were carried out on the arteries of smooth muscle cell-specific Bcl11b-knockout mice at 3, 7, 28 days after tamoxifen injections as well as on the smooth muscle cells isolated from the aorta of Bcl11b-floxed mice that were cultured and inactivated by Cre recombinase using adenoviral vectors. We analysed mice with Bcl11b deletion in vascular SMC (Bcl11b-SMKO). There is no difference between control and mutant mice at the macroscopic level 3 days after Bcl11b KO induction, however, 7 days after Bcl11b inactivation, 70% of the Bcl11b-SMKO mice showed signs of haemorrhage in the distal part of the thoracic aorta near the abdominal aorta. The histological examination of thoracic aorta at day 7 indicated the presence of "bumpy region" in the mutant aorta, these areas seem to be covered by a thicker layer of extracellular matrix and the presence of IgG positive cells, indicating that cell death via necroptosis is occurring in this tissue. Our preliminary results from smooth muscle cell culture indicate higher cell death rate in the mutant cells compared to control cells. Our data suggest a primary effect of Bcl11b inactivation on cell death, probably through necroptosis. The mechanisms linked to cell death induced by Bcl11b loss is under investigation. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) displays an increased venous and arterial thrombotic risk despite the common occurrence of intestinal bleeding. While some of the mechanisms leading to these thrombotic complications have been studied, other specific changes in the hemostasis profile of IBD patients have been less explored. One such example relates to von Willebrand factor (VWF) whose plasma levels have been reported to be modulated in IBD. Von Willebrand factor is a plasma glycoprotein crucial for hemostatic functions via roles both in platelet function and coagulation. High plasma VWF is a known risk factor for venous thromboembolism. In addition to its canonical roles in hemostasis, VWF is known to be directly or indirectly involved in other vascular processes such as maintenance of endothelial barrier integrity or proliferation of vascular smooth muscle cells. The purpose of this review is to recapitulate and update the existing data about VWF biology in IBD and to highlight its role both in the existing procoagulant phenotype and in vascular alterations that may occur in IBD., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The elastic properties of conductance arteries are one of the most important hemodynamic functions in the body, and data continue to emerge regarding the importance of their dysfunction in vascular aging and a range of cardiovascular diseases. Here, we provide new insight into the integrative physiology of arterial stiffening and its clinical consequence. We also comprehensively review progress made on pathways/molecules that appear today as important basic determinants of arterial stiffness, particularly those mediating the vascular smooth muscle cell (VSMC) contractility, plasticity and stiffness. We focus on membrane and nuclear mechanotransduction, clearance function of the vascular wall, phenotypic switching of VSMCs, immunoinflammatory stimuli and epigenetic mechanisms. Finally, we discuss the most important advances of the latest clinical studies that revisit the classical therapeutic concepts of arterial stiffness and lead to a patient-by-patient strategy according to cardiovascular risk exposure and underlying disease.

Aims: α v integrins are implicated in fibrosis in a number of organs through their ability to activate TGF-β. However their role in vascular fibrosis and collagen accumulation is only partially understood. Here we have used α v conditional knockout mice and cell lines to determine how α v contributes to vascular smooth muscle cell (VSMC) function in vascular fibrosis and the role of TGF-β in that process., Methods and Results: Angiotensin II (Ang II) treatment causes upregulation of α v and β 3 expression in the vessel wall, associated with increased collagen deposition. We found that deletion of α v integrin subunit from VSMCs (α v SMKO ) protected mice against angiotensin II-induced collagen production and assembly. Transcriptomic analysis of the vessel wall in α v SMKO mice and controls identified a significant reduction in expression of fibrosis and related genes in α v SMKO mice. In contrast, α v SMKO mice showed prolonged expression of CD109, which is known to affect TGF-β signalling. Using cultured mouse and human VSMCs, we showed that overexpression of CD109 phenocopied knockdown of α v integrin, attenuating collagen expression, TGF-β activation, and Smad2/3 signalling in response to angiotensin II or TGF-β stimulation. CD109 and TGF-β receptor were internalized in early endosomes., Conclusion: We identify a role for VSMC α v integrin in vascular fibrosis and show that α v acts in concert with CD109 to regulate TGF-β signalling., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Amine oxidase copper containing 3 (AOC3) displays adhesion between leukocytes and endothelial cells and enzymatic functions. Given its controversial role in atherogenesis, we proposed to investigate the involvement of AOC3 in the formation of atherosclerotic plaques in ApoE -/- AOC3 -/- mice and human coronary arteries., Methods: Lesions, contractile markers, and AOC3 were studied in aortic tissues from 15- and 25-week-old mice and different stages of human coronary atherosclerotic arteries by immunohistochemistry (IHC) and/or western blot. Human VSMCs, treated or not with LJP1586, an AOC3 inhibitor, were used to measure differentiation markers by qPCR. AOC3 co-localization with specific cell markers was studied by using confocal microscopy in mice and human samples., Results: At 15 weeks old, the absence of AOC3 was associated with increased lesion size, α-SMA, and CD3 staining in the plaque independently of a cholesterol modification. At 25 weeks old, advanced plaques were larger with equivalent staining for α-SMA while CD3 increased in the media from ApoE -/- AOC3 -/- mice. At both ages, the macrophage content of the lesion was not modified. Contractile markers decreased whereas MCP-1 appeared augmented only in the 15-week-old ApoE -/- AOC3. AOC3 is mainly expressed by mice and human VSMC is slightly expressed by endothelium but not by macrophages., Conclusion: AOC3 knock-out increased atherosclerotic plaques at an early stage related to a VSMC dedifferentiation associated with a higher T cells recruitment in plaques explained by the MCP-1 augmentation. This suggests that AOC3 may have an important role in atherosclerosis independent of its canonical inflammatory effect. The dual role of AOC3 impacts therapeutic strategies using pharmacological regulators of SSAO activity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Filip, Taleb, Bascetin, Jahangiri, Bardin, Lerognon, Fève, Lacolley, Jalkanen and Mercier.)

Objectives: Although cardiovascular benefits of β 1 -adrenergic receptor blockade have been described in sepsis, little is known about its impact on the adaptive immune response, specifically CD4 T cells. Herein, we study the effects of β 1 -adrenergic receptor modulation on CD4 T-cell function in a murine model of sepsis., Design: Experimental study., Setting: University laboratory., Subjects: C57BL/6 mice., Interventions: High-grade sepsis was induced by cecal ligation and puncture in wild-type mice (β 1+/+ ) with or without esmolol (a selective β 1 -adrenergic receptor blocker) or in β 1 -adrenergic receptor knockout mice (β 1-/- ). At 18 hours after surgery, echocardiography was performed with blood and spleen collected to analyze lymphocyte function., Measurements and Main Results: At 18 hours, β 1+/+ cecal ligation and puncture mice exhibited characteristics of high-grade sepsis and three surrogate markers of immunosuppression, namely decreased splenic CD4 T cells, reduced CD4 T-cell proliferation, and increased regulatory T lymphocyte cell proportions. Pharmacologic and genetic β 1 -adrenergic receptor blockade reversed the impact of sepsis on CD4 T and regulatory T lymphocyte proportions and maintained CD4 T-cell proliferative capacity. β 1 -adrenergic receptor blocked cecal ligation and puncture mice also exhibited a global decrease in both pro- and anti-inflammatory mediators and improved in vivo cardiovascular efficiency with maintained cardiac power index despite the expected decrease in heart rate., Conclusions: β 1 -adrenergic receptor activation enhances regulatory T lymphocyte inhibitory function and thus contributes to sepsis-induced immunosuppression. This can be attenuated by β 1 -adrenergic receptor blockade, suggesting a potential immunoregulatory role for this therapy in the management of sepsis., Competing Interests: Dr. Durand’s institution received funding from the Fondation pour la Recherche Médicale (FRM grant number ECO20170637495). Dr. Asfar received funding from GlaxoSmithKline. Dr. Singer’s institution received funding from Biotest, Deltex, and NewB; he received funding from Biotest, Biomerieux, Fresenius, General Electric, Nestle, NewB Diagnostics, Pfizer, and Shionogi. Drs. Singer and Levy received funding from Amomed. Dr. Singer received funding from Roche. Dr. Levy received funding from Gettinge, Novartis, Baxter, Amomed, Orion, and Sanofi. Dr. Kimmoun received funding from Aguettant. Dr. Glenn Chousterman received fees as a member of an advisory board from Roche Diagnostics. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: In APS, precise evaluation of thrombotic risk is a major challenge. Different players, such as activated protein C (APC) resistance or neutrophil extracellular traps (NETs) contribute to the risk of thrombosis. Nevertheless, no study has investigated the interaction between these actors. The main objective of this study was to investigate the relation between NETs and APC resistance., Methods: We designed a cross-sectional study including APS/antiphospholipid antibodies (aPL) patients and patients with autoimmune diseases (AID). We performed thrombin generation tests without and with APC to determine APC resistance. To evaluate circulating NETs, we measured plasma levels of MPO-DNA complexes and cell-free DNA with ELISA., Results: We recruited 117 patients with definite APS/aPL or AID. We found a positive correlation between NETs and APC resistance, in APS patients and specifically in patients with high thrombotic risk, displaying LA or positivity of all three aPL tests (triple+), or anti-domain I IgG (aDI+). All these patient subgroups had increased NETs concentrations and APC resistance. As the risk profile for thrombosis increased, the relationship between NETs and APC resistance was stronger., Conclusion: We have shown that NETs participate in the hypercoagulable state of APS patients by contributing to APC resistance, in particular in high-risk patients. In these most at-risk patients, a targeted action on NETs could reduce APC resistance and constitute a new therapeutic approach in the treatment of APS patients in addition to antithrombotic therapy., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Chronic inflammation in atherosclerosis reflects a failure in the resolution of inflammation. Pro-resolving lipid mediators derived from omega-3 fatty acids reduce the development of atherosclerosis in murine models. The aim of the present study was to decipher the role of the specialized proresolving mediator (SPM) resolvin D2 (RvD2) in atherosclerosis and its signaling through the G-protein coupled receptor (GPR) 18. The ligand and receptor were detected in human coronary arteries in relation to the presence of atherosclerotic lesions and its cellular components. Importantly, RvD2 levels were significantly higher in atherosclerotic compared with healthy human coronary arteries. Furthermore, apolipoprotein E (ApoE) deficient hyperlipidemic mice were treated with either RvD2 or vehicle in the absence and presence of the GPR18 antagonist O-1918. RvD2 significantly reduced atherosclerosis, necrotic core area, and pro-inflammatory macrophage marker expression. RvD2 in addition enhanced macrophage phagocytosis. The beneficial effects of RvD2 were not observed in the presence of O-1918. Taken together, these results provide evidence of atheroprotective pro-resolving signalling through the RvD2-GPR18 axis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Von Willebrand factor (VWF) is a plasma glycoprotein involved in primary haemostasis, while also having additional roles beyond haemostasis namely in cancer, inflammation, angiogenesis, and potentially in vascular smooth muscle cell (VSMC) proliferation. Here, we addressed how VWF modulates VSMC proliferation and investigated the underlying molecular pathways and the in vivo pathophysiological relevance., Methods and Results: VWF induced proliferation of human aortic VSMCs and also promoted VSMC migration. Treatment of cells with a siRNA against αv integrin or the RGT-peptide blocking αvβ3 signalling abolished proliferation. However, VWF did not bind to αvβ3 on VSMCs through its RGD-motif. Rather, we identified the VWF A2 domain as the region mediating binding to the cells. We hypothesized the involvement of a member of the LDL-related receptor protein (LRP) family due to their known ability to act as co-receptors. Using the universal LRP-inhibitor receptor-associated protein, we confirmed LRP-mediated VSMC proliferation. siRNA experiments and confocal fluorescence microscopy identified LRP4 as the VWF-counterreceptor on VSMCs. Also co-localization between αvβ3 and LRP4 was observed via proximity ligation analysis and immuno-precipitation experiments. The pathophysiological relevance of our data was supported by VWF-deficient mice having significantly reduced hyperplasia in carotid artery ligation and artery femoral denudation models. In wild-type mice, infiltration of VWF in intimal regions enriched in proliferating VSMCs was found. Interestingly, also analysis of human atherosclerotic lesions showed abundant VWF accumulation in VSMC-proliferating rich intimal areas., Conclusion: VWF mediates VSMC proliferation through a mechanism involving A2 domain binding to the LRP4 receptor and integrin αvβ3 signalling. Our findings provide new insights into the mechanisms that drive physiological repair and pathological hyperplasia of the arterial vessel wall. In addition, the VWF/LRP4-axis may represent a novel therapeutic target to modulate VSMC proliferation., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Patients with inflammatory bowel disease (IBD) are at increased risk of thrombotic events. Therapies for IBD have the potential to modulate this risk. The aims of this Evidence-Based Guideline were to summarize available evidence and to provide practical recommendations regarding epidemiological aspects, prevention and drug-related risks of venous and arterial thrombotic events in patients with IBD. A virtual meeting took place in May 2020 involving 14 international IBD experts and 3 thrombosis experts from 12 countries. Proposed statements were voted upon in an anonymous manner. Agreement was defined as at least 75% of participants voting as 'fully agree' or 'mostly agree' with each statement. For each statement, the level of evidence was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) grading system. Consensus was reached for 19 statements. Patients with IBD harbour an increased risk of venous and arterial thrombotic events. Thromboprophylaxis is indicated during hospitalization of any cause in patients with IBD. Disease activity is a modifiable risk factor in patients with IBD, and physicians should aim to achieve deep remission to reduce the risk. Exposure to steroids should be limited. Antitumour necrosis factor agents might be associated with a reduced risk of thrombotic events., (© 2021. The Author(s).)

Cardiovascular diseases remain an age-related pathology in both men and women. These pathologies are 3-fold more frequent in men than in women before menopause, although this difference progressively decreases after menopause. The vasculoprotective role of estrogens are well established before menopause, but the consequences of their abrupt decline on the cardiovascular risk at menopause remain debated. In this review, we will attempt to summarize the main clinical and experimental studies reporting the protective effects of estrogens against cardiovascular diseases, with a particular focus on atherosclerosis, and the impact of aging and estrogen deprivation on their endothelial actions. The arterial actions of estrogens, but also part of that of androgens through their aromatization into estrogens, are mediated by the estrogen receptor (ER)α and ERβ. ERs belong to the nuclear receptor family and act by transcriptional regulation in the nucleus, but also exert non-genomic/extranuclear actions. Beside the decline of estrogens at menopause, abnormalities in the expression and/or function of ERs in the tissues, and particularly in arteries, could contribute to the failure of classic estrogens to protect arteries during aging. Finally, we will discuss how recent insights in the mechanisms of action of ERα could contribute to optimize the hormonal treatment of the menopause., Competing Interests: The laboratory received support from Mithra Pharmaceuticals for preclinical studies on estetrol., (Copyright © 2021 Davezac, Buscato, Zahreddine, Lacolley, Henrion, Lenfant, Arnal and Fontaine.)