Inflammatory Vascular Disorders Research Articles

Cas clinique : cas rare d'un faux anévrisme spontané de l'artère fémorale superficielle révélant une maladie de Behçet chez un jeune patient

Behçet's disease is a chronic inflammatory vascular disorder that can affect arteries and veins of various sizes. Arterial involvement, which plays a significant prognostic role, requires a treatment approach involving corticosteroids, immunosuppressants, and potentially surgical or endovascular procedures. This article presents the case of a young man diagnosed with Behçet's disease, manifested by a spontaneous pseudoaneurysm in the superficial femoral artery. The patient underwent surgical intervention to remove the pseudoaneurysm and restore circulation using a venous graft. This case underscores the importance of considering Behçet's disease in vascular manifestations.

Renal Limited Anti-Neutrophil Cytoplasmic Antibody Associated Vasculitis: A Case Report

Background: Renal Limited Vasculitis (RLV) is a localized autoimmune vascular inflammatory disorder that is part of the Pauci Immune Glomerulonephritis (PIGN) spectrum. Over 90% of PIGN patients have circulating Anti-Neutrophil Cytoplasmic Antibodies (ANCA Ab). Anti-Neutrophil Cytoplasmic Antibody (ANCA) associated vasculitides are a heterogeneous group of multisystemic autoimmune disorders with distinct pathological findings. They are characterized by widespread inflammation of vessels according to their size, their location, and their serotypes based on the presence or absence of ANCA antibodies, namely Myeloperoxidase (MPO-ANCA), Proteinase-3 (PR3-ANCA) or simply ANCA negative, if no antibodies are found. RLV is characterized by antibody positivity to myeloperoxidase in the majority of cases. Case Report: A 77-year-old Caucasian female was admitted with altered mental status and laboratory evidence of renal function compromise consistent with non-oliguric acute renal failure. Imaging and renal biopsy resulted in a diagnosis of pauci-immune glomerulonephritis consistent with MPO-ANCA vasculitis with a subtype that was associated with necrotizing arteritis, a severe form of the disease. She was placed on hemodialysis, intravenous cyclophosphamide, and oral prednisone, and entered remission. Conclusion: A high level of suspicion and familiarity with clinical signs and symptoms are critical in distinguishing primary RPGN subtypes from other types of ANCA-associated small vessel vasculitis. If left untreated, renal limited vasculitis can progress to widespread systemic involvement and become fatal.

Gastrointestinal Behçet's disease: Manifestations, diagnosis, and management

Behçet's disease (BD) is a rare, inflammatory vascular disorder with recurrent oral and genital aphthous ulcers, along with ocular and cutaneous manifestations. Gastrointestinal (GI) BD may involve any portion of the GI tract. However, it is commonly described in the terminal ileum, followed by the ileocecal region. Diagnosis is challenging given lack of pathognomonic tests; therefore, it is based on clinical criteria. Management of intestinal BD includes different classes of medications including corticosteroids, 5-aminosalicylic acid, immunomodulators, and anti-tumor necrosis factor alpha monoclonal antibody agents. In this review, we aim to focus on intestinal BD and provide details of clinical manifestations, diagnosis and therapeutic options of intestinal BD from gastroenterology viewpoint.

Research advances in genetic polymorphisms in Kawasaki disease

Kawasaki disease (KD) is a systemic inflammatory vascular disorder that predominantly affects children and is the leading cause of acquired heart disease in children. Although the etiology of this disease remains unclear, genome-wide association and genome-wide linkage studies have shown that some susceptible genes and chromosomal regions are associated with the development and progression of KD. With the advancement of high-throughput DNA sequencing techniques, more and more genomic information related to KD is being discovered. Understanding the genes involved in the pathogenesis of KD may provide novel insights into the diagnosis and treatment of KD. By analyzing related articles and summarizing related research advances, this article mainly discusses the T cell activation-enhancing genes that have been confirmed to be closely associated with the development and progression of KD and reveals their association with the pathogenesis of KD and coronary artery lesions.

T1-Weighted 3D-Black-Blood-Imaging in Giant-Cell Arteriitis Temporalis and Extracranial Arteritis: A Case Report

Giant-cell arteritis (GCA) is a common vascular inflammatory disorder that often presents with clinical symptoms necessitating prompt diagnosis. Delay in diagnosis can lead to severe patient impairment. This case report highlights the utility of contrast-enhanced T1-weighted 3D-Black Blood (BB) imaging in the diagnostic work-up of GCA, along with its histological correlations. We present the case of an 81-year-old male patient with clinical symptoms suggestive of bilateral temporal arteritis. The patient underwent cranial magnetic resonance imaging (MRI) with contrast-enhanced T1-weighted 3D-BB sequence, which revealed wall-enhancement with perivascular "stranding" of both temporal arteries and their branches, luminal narrowing, and pathological enhancement of the vertebral and basilar arteries. Histological analysis after biopsy confirmed a diagnosis of temporal arteritis. This case report emphasizes the valuable role of contrast-enhanced T1-weighted 3D-BB imaging in the diagnosis of GCA, providing higher resolution and flow signal suppression. The observed "perivascular stranding" and histological findings contribute to our understanding of the disease. Radiologists should consider incorporating this imaging sequence into their diagnostic protocols when GCA is suspected.

The burden of gastrointestinal diseases in Japan, 1990-2019, and projections for 2035.

Disease burden estimation allows clinicians and policymakers to plan for future healthcare needs. Although advances have been made in gastroenterology, as Japan has an aging population, disease burden assessment is important. We aimed to report gastrointestinal disease burden in Japan since 1990 and project changes through to 2035. This descriptive study examined the crude and age-standardized rates of prevalence, mortality, and disability-adjusted life years (DALYs) of 22 gastrointestinal diseases between 1990 and 2019. We used data from the Global Burden of Disease study 2019. We calculated the expected disease burden of gastrointestinal diseases by 2035 using an autoregressive integrated moving average. Since 1990, cancer has accounted for most gastrointestinal disease-related causes of mortality and DALYs in Japan (77.1% and 71.2% in 1990, 79.2% and 73.7% in 2019, respectively). Although cancer-associated age-standardized mortality rates and DALYs have shown a decreasing trend, the crude rates have increased, suggesting that an aging society has a significant impact on the disease burden in Japan. Therefore, the overall gastrointestinal disease burden is expected to increase by 2035. Noncancerous chronic diseases with a high burden included cirrhosis, biliary disease, ileus, gastroesophageal reflux disorder, hernia, inflammatory bowel disease, enteric infections, and vascular intestinal disorders. In cirrhosis, the DALYs for hepatitis C decreased and the prevalence of non-alcoholic steatohepatitis increased. In the super-aging Japanese society, the burden of gastrointestinal diseases is expected to increase in the coming years. Colorectal, gastric, pancreatic, and liver cancers are the focus of early detection and treatment.

Mesenteric Inflammatory Veno-Occlusive Disease of the Colon: An Under-Recognized Entity - A Case Report

Isolated nonthrombotic venulitis of the colon with concomitant ischemic injury, also known as mesenteric inflammatory veno-occlusive disease (MIVOD), is a rare inflammatory vascular disorder of unknown etiology. First described in 1994, there are only about 34 cases in the literature. We report a 25-year-old woman who presented with loose stools and abdominal pain of 3-week duration. Investigations revealed eosinophilia. Endoscopy showed erosion and ulcers of the gastrointestinal tract, with mucosal biopsies showing features of ischemic injury. Computed tomography showed an edematous and thickened colonic wall with impending perforation, hence, a subtotal colectomy was performed. The patient, however, had a cardiac arrest and expired despite adequate measures. The resection specimen was consistent with a diagnosis of MIVOD. As the clinical and radiological features of MIVOD are nonspecific and overlap with inflammatory bowel disease or mesenteric ischemic disorders, histopathological examination of the resection specimen is the mainstay for its diagnosis. We believe this is the only other case in the literature of MIVOD with eosinophil predominance.

Vascular adhesion protein-1 (VAP-1) in vascular inflammatory diseases.

Vascular adhesion protein-1 (VAP-1) also known as amino oxidase copper containing 3 (AOC3) is a pro-inflammatory and versatile molecule with adhesive and enzymatic properties. VAP-1 is a primary amine oxidase belonging to the semicarbazide-sensitive amine oxidase (SSAO) family, which catalyzes the oxidation of primary amines leading to the production of ammonium, formaldehyde, methylglyoxal, and hydrogen peroxide. VAP-1 is mainly expressed by endothelial cells, smooth muscle cells, adipocytes and pericytes. It is involved in a repertoire of biological functions, e.g., immune cell extravasation, angiogenesis, and vascularization. Research into VAP-1 has intensified within the last decade on its role as a novel clinical biomarker and as a potential therapeutic target of vascular inflammatory disorders such as atherosclerosis, stroke, diabetes, neurovascular disorders (e.g., Alzheimer's Disease), hepatic disease (e.g., non-alcoholic steatohepatitis), and skin conditions (e.g., psoriasis). This is the most up-to-date and comprehensive review on VAP-1 focusing on the translational aspects of VAP-1. Compared to recent reviews, our review provides novel insights on VAP-1 and heart failure, stroke and frailty, diabetes, endometriosis, osteoarthritis, COVID-19, conjunctivitis associated systemic lupus erythematosus, hematopoietic stem cells, gliomas, treatment of colorectal cancer with a novel VAP-1 inhibitor (U-V269), promoting recovery of motor functions and habit learning with a novel VAP-1 inhibitor (PXS-4681A), and 68Ga-DOTA-Siglec-9, a labelled peptide of Siglec-9 (a VAP-1 ligand), which appears to be a safe PET tracer for inflammation in rheumatoid arthritis. Finally, we present the emerging role of VAP-1 in pregnancy as a gatekeeper of immune cells, which are critical for spiral arterial remodeling, the deficiency of which could lead to vascular disorders of pregnancy such as preeclampsia. Future research should prioritize clinical trials on VAP-1 small-molecule inhibitors and monoclonal antibodies, thus, maximizing the potential of VAP-1 targeted therapy as well as research into sVAP-1 as a clinical biomarker of diseases and its prognosis.

Resolvin E1 attenuates endothelial senescence induced by doxorubicin through the modulation of NLRP3 inflammasome activation.

Introduction: Vascular aging is associated with endothelial cell senescence, favoring low-grade inflammation, endothelial dysfunction, and cardiovascular diseases. Cell senescence arises from a wide variety of endogenous and exogenous stressors including some anticancer agents such as doxorubicin. Recently, doxorubicin was linked to the innate immunity component NLRP3 inflammasome which is implicated in many vascular inflammatory disorders. There is a need for therapeutic tools to help cancer patients who have been exposed to cardiovascular toxic chemotherapy averting premature vascular complications. We investigated whether resolvin E1 (RvE1), an endogenous lipid mediator of the inflammation resolution phase, could prevent doxorubicin-induced senescence in cultured human umbilical veins endothelial cells (HUVEC) with focus on a potential involvement of the NLRP3 inflammasome. Materials and Methods: Cell senescence was quantified by senescence-associated-β-galactosidase (SA-β-gal) staining. The expression of senescence markers (γH2AX, p21, p53) and inflammatory markers (pP65, NLRP3) was determined via Western blot. NLRP3 inflammasome activation was determined by visualizing the formation of ASC specks by indirect immunofluorescence. Results: Doxorubicin (25 nmol/L) augmented the number of SA-β-gal positive HUVEC and the levels of γH2AX, p21 and p53 which were all reduced by RvE1 (10 nmol/L). In doxorubicin-treated cells, RvE1 further reduced the expression of pP65 and NLRP3 proteins and the formation of ASC specks as did the inflammasome assembly inhibitor MCC950 (1µmol/L). Additionally, both MCC950 and interleukin-1 receptor inhibitor anakinra diminished SA-β-gal positive staining induced by doxorubicin. Conclusion: RvE1 offers a novel therapeutic approach against doxorubicin-induced cardiovascular toxicity and subsequent age-related vascular disorders by counteracting endothelial senescence through the modulation of NLRP3- inflammasome activation.

Brainstem lesions: MRI review of standard morphological sequences.

MRI signal changes in the brainstem are observed in a multitude of disorders including vascular diseases, neoplastic lesions, degenerative diseases, inflammatory disorders, metabolic diseases, infections, and trauma. In some diseases, brainstem involvement is typical and sometimes isolated, while in other diseases, brainstem lesions are only observed occasionally in the presence of other typical extra-brainstem abnormalities. In this review, we will discuss the MRI characteristics of brainstem lesions observed in different disorders associated with frequent and less frequent brainstem involvement. Identification of the origin of the brainstem lesion depends on the exact localisation of the lesion(s) inside the brainstem, the presence and the characteristics of associated lesions seen outside the brainstem, the signal changes on different MRI sequences, the evolution over time of the radiological abnormalities, the history and clinical state of the patient, and other radiological and non-radiological examinations.

Abstract 12458: Protein L-isoaspartyl O-methyltransferase Attenuates Endothelial Activation Through Inhibitory Interaction With TRAF6 and ICAM1

Introduction: Endothelial activation provokes expression of cell surface adhesion molecules to facilitate circulating leukocyte diapedesis, which demands rigorous surveillance to prevent excessive inflammation response and host damage. As a repair enzyme, protein L-isoaspartyl O-methyltransferase (PIMT) methylates and converts isoaspartyl (isoAsp) residuals back to conventional form to avoid protein damage and aging. However, the role of PIMT in vascular homeostasis remains to be delineated. Methods and Results: Murine acute lung injury (ALI) model was deployed to investigate the significance of PIMT in endothelial activation and vascular inflammation. Results showed that mice harboring heterozygous deletion of PIMT displayed exacerbated pulmonary vascular inflammation. Ectopic overexpression of PIMT protected endothelial cells against endotoxin stimulated endothelial activation, as characterized by attenuated expression of inflammatory cytokines, chemokines, cell adhesion molecules and monocytic adherence to activated endothelial cells. Mechanistically, we found that PIMT inhibits lipopolysaccharide (LPS)-induced endothelial NF-κB transactivation. Tumor necrosis factor receptor-associated factor 6 (TRAF6) was identified as a dynamic binding partner and substrate of PIMT in regulating NF-κB signaling. PIMT catalyzed methylation at an asparagine derived isoAsp residual of TRAF6 directly prevented its oligomerization and auto-ubiquitination. Strikingly, we also found that PIMT specifically impeded N-glycosylation at multiple sites of endothelial intercellular adhesion molecule 1 (ICAM1). The hypo-glycosylated ICAM1 elicited impaired interaction with cell skeletal and reduced stability, which further diminished endothelial activation. Conclusions: PIMT negatively modulates endothelial activation through restricting activation of TRAF6 and inhibiting N-glycosylation of adhesion molecules. Our study provides a novel insight into the role of protein O-methylation in regulating endothelial inflammation and suggest that targeting PIMT may have potential therapeutic applications in treating inflammatory vascular disorders.

Anatomical Basis of Clinical Manifestations Seen in Cavernous Sinus Syndrome: A Narrative Review

Pathology involving the Cavernous Sinus (CS), generally referred to as Cavernous Sinus Syndrome (CSS), can arise from vascular disorders, neoplasms, infections, and non-infectious inflammatory disorders. An acute understanding of the CS and its regional anatomical structures is therefore pertinent in expounding the highly variable clinical manifestations seen in CSS as well as laying the groundwork for surgical intervention. Though the neuroanatomy of the cavernous sinus has been substantially chronicled in literature, their correlation to clinical signs has only been minimally described. This narrative review serves to address this knowledge gap and aims to comprehensively correlate the clinical manifestations of CSS with the relevant neuroanatomy, thereby allowing medical practitioners to better navigate the diagnostic quandary. We conducted a scoping review of the literature concerning CS anatomy and CSS, complied through MEDLINE/OVID and cross-referencing of articles on PubMed and Google Scholar with the keywords cavernous sinus, cavernous sinus syndrome, clinical signs/manifestations, neuroanatomy, CS pathology, Cavernous Sinus Thrombus (CST) and cavernous sinus neoplasms/tumours.

Imaging the pediatric retina: An overview.

Recent decade has seen a shift in the causes of childhood blinding diseases from anterior segment to retinal disease in both developed and developing countries. The common retinal disorders are retinopathy of prematurity and vitreoretinal infections in neonates, congenital anomalies in infants, and vascular retinopathies including type 1 diabetes, tumors, and inherited retinal diseases in children (up to 12 years). Retinal imaging helps in diagnosis, management, follow up and prognostication in all these disorders. These imaging modalities include fundus photography, fluorescein angiography, ultrasonography, retinal vascular and structural studies, and electrodiagnosis. Over the decades there has been tremendous advances both in design (compact, multifunctional, tele-consult capable) and technology (wide- and ultra-wide field and noninvasive retinal angiography). These new advances have application in most of the pediatric retinal diseases though at most times the designs of new devices have remained confined to use in adults. Poor patient cooperation and insufficient attention span in children demand careful crafting of the devices. The newer attempts of hand-held retinal diagnostic devices are welcome additions in this direction. While much has been done, there is still much to do in the coming years. One of the compelling and immediate needs is the pediatric version of optical coherence tomography angiography. These needs and demands would increase many folds in future. A sound policy could be the simultaneous development of adult and pediatric version of all ophthalmic diagnostic devices, coupled with capacity building of trained medical personnel.

Smooth Muscle Cell Derived Microparticles Acts as Autocrine Activation of Smooth Muscle Cell Proliferation by Mitogen Associated Protein Kinase Upregulation.

Microparticles (MP); also know as microvesicles are extracellular vesicles (0.1 to 1.0 μm) released by cells in response to cell activation or apoptosis. The high level of circulating MP is one of the important indicators of altered vascular function. Vascular smooth muscle cell (VSMC) derived MP could mediate proliferation and migration of VSMC leading to vascular inflammation. Proliferation of VSMC is mediated by mitogen associated protein kinase (MAPK) and proliferation cell nuclei antigen (PCNA) signaling pathway whereas migration is mediated by metalloproteinase and cytoskeletal remodeling pathway. In this study, VSMC-MP were isolated from confluent VSMC stimulated with tumor necrosis factor (TNF)-α. VSMC-MP were treated to VSMC to investigate the VSMC proliferation marker using in vitro assay. In comparison to normal (VSMC-MP untreated group), VSMC-MP treatment results in proliferation of VSMC as revealed by MTT assay. VSMC-MP and TNF-α induce proliferation by 34% and 67% respectively. VSMC-MP also induce over expression of PCNA in both immuno-fluorescence and western blot experiment. VSMC-MP and TNF-α increase the PCNA expression by 1.86-fold and 1.95-fold respectively. Similarly, VSMC-MP treatment results in over expression of MAPK pathway protein expression in VSMC. As compared to normal, the MAPK protein (pERK1/2, pP38 and pJNK) were increased by 1.41-fold, 1.42-fold and 1.48-fold, respectively in VSMC-MP treated VSMC. Our results provide the evidence of VSMC-MP involvement in proliferation of VSMC. Thus, VSMC-MP could be considered as a potential marker of vascular inflammatory disorder such as atherosclerosis.

Protective Effect of Tetrahydroquinolines from the Edible Insect Allomyrina dichotoma on LPS-Induced Vascular Inflammatory Responses.

The larva of Allomyrina dichotoma (family Scarabaeidae) is an edible insect that is registered in the Korean Food Standards Codex as a food resource. The chemical study on the larvae of A. dichotoma resulted in the isolation of three new tetrahydroquinolines, allomyrinaines A–C (1–3), one new dopamine derivative, allomyrinamide A (4), and four known compounds (5–8). The structures were elucidated on the basis of 1D and 2D nuclear magnetic resonance (NMR) and MS spectroscopic data analysis. Allomyrinaines A–C (1–3) possessed three stereogenic centers at C-2, C-3, and C-4, whose relative configurations were determined by analyses of the coupling constants and the nuclear Overhauser enhancement spectroscopy (NOESY) data, as well as DP4+ calculation. The anti-inflammatory effects of compounds 1–4 were evaluated in human endothelial cells. Allomyrinaines A–C (1–3) could stabilize vascular barrier integrity on lipopolysaccharide (LPS)-induced vascular inflammation via inhibition of the nuclear factor-κB (NF-κB) pathway. The physiologically relevant concentration was confirmed by Q-TOF-MS-based quantitative analysis on allomyrinaines A–C in crude extract. This study suggests that allomyrinaines A–C (1–3) are bioactive constituents of A. dichotoma to treat vascular inflammatory disorder.

Ca2+ release-activated Ca2+ channels are responsible for histamine-induced Ca2+ entry, permeability increase, and interleukin synthesis in lymphatic endothelial cells.

The lymphatic functions in maintaining lymph transport, and immune surveillance can be impaired by infections and inflammation, thereby causing debilitating disorders, such as lymphedema and inflammatory bowel disease. Histamine is a key inflammatory mediator known to trigger vasodilation and vessel hyperpermeability upon binding to its receptors and evoking intracellular Ca2+ ([Ca2+]i) dynamics for downstream signal transductions. However, the exact molecular mechanisms beneath the [Ca2+]i dynamics and the downstream cellular effects have not been elucidated in the lymphatic system. Here, we show that Ca2+ release-activated Ca2+ (CRAC) channels, formed by Orai1 and stromal interaction molecule 1 (STIM1) proteins, are required for the histamine-elicited Ca2+ signaling in human dermal lymphatic endothelial cells (HDLECs). Blockers or antagonists against CRAC channels, phospholipase C, and H1R receptors can all significantly diminish the histamine-evoked [Ca2+]i dynamics in lymphatic endothelial cells (LECs), while short interfering RNA-mediated knockdown of endogenous Orai1 or STIM1 also abolished the Ca2+ entry upon histamine stimulation in LECs. Furthermore, we find that histamine compromises the lymphatic endothelial barrier function by increasing the intercellular permeability and disrupting vascular endothelial-cadherin integrity, which is remarkably attenuated by CRAC channel blockers. Additionally, the upregulated expression of inflammatory cytokines, IL-6 and IL-8, after histamine stimulation was abolished by silencing Orai1 or STIM1 with RNAi in LECs. Taken together, our data demonstrated the essential role of CRAC channels in mediating the [Ca2+]i signaling and downstream endothelial barrier and inflammatory functions induced by histamine in the LECs, suggesting a promising potential to relieve histamine-triggered vascular leakage and inflammatory disorders in the lymphatics by targeting CRAC channel functions.

A Possible Role of Amyloidogenic Blood Clotting in the Evolving Haemodynamics of Female Migraine-With-Aura: Results From a Pilot Study.

Introduction: Migraine is a debilitating primary headache disorder with a poorly understood aetiology. An extensive body of literature supports the theory of migraine as a systemic vascular inflammatory disorder characterised by endothelial dysfunction. It is also well-known that chronic inflammation results in an excessive burden of oxidative stress and therefore cellular dysfunction. In this study the effects of excessive oxidative stress through the phases of female migraine-with-aura (FMA) were evaluated by examining the health of the systems of haemostasis.Methods: Blood was obtained from 11 FMA patients at baseline and during the headache phase of migraine, as well as from 8 healthy age-matched female controls. Samples were analysed using thromboelastography (TEG) to evaluate viscoelastic profiles, light microscopy for erythrocyte morphology, Scanning Electron Microscopy (SEM) for erythrocyte and fibrin clot structure, confocal microscopy for β-amyloid detection in fibrin clots.Results: Viscoelastic profiles from platelet poor plasma showed decreased clot reaction times in FMA at baseline (95% CI [5.56, 8.41]) vs. control (95% CI [7.22, 11.68]); as well as decreased time to maximum thrombus generation for the same comparison (95% CI [6.78, 10.20] vs. [8.90, 12.96]). Morphological analysis of erythrocytes indicated widespread macrocytosis, poikilocytosis and eryptosis in the migraineurs. Analysis of fibrin networks indicated that this hypercoagulability may be a result of aberrant fibrin polymerisation kinetics caused by the adoption of a β-amyloid conformation of fibrin(ogen).Conclusion: The results reaffirm the hypercoagulable state in migraine, and would suggest that this state is most likely a result of a systemic inflammatory state which induces oxidative damage to both erythrocytes and fibrin(ogen) in female episodic migraine-with-aura. Furthermore, if the amylodogenic changes to fibrin(ogen) were observed in a larger cohort, this would support theories of micro-embolisation in migraine-with-aura.

Targeting Coagulation Factor Xa Promotes Regression of Advanced Atherosclerosis in Apolipoprotein-E Deficient Mice

Atherosclerosis is a progressive inflammatory vascular disorder, complicated by plaque rupture and subsequently atherothrombosis. In vitro studies indicate that key clotting proteases, such as factor Xa (FXa), can promote atherosclerosis, presumably mediated through protease activated receptors (PARs). Although experimental studies showed reduced onset of atherosclerosis upon FXa inhibition, the effect on pre-existing plaques has never been studied. Therefore, we investigated effects of FXa inhibition by rivaroxaban on both newly-formed and pre-existing atherosclerotic plaques in apolipoprotein-e deficient (ApoE−/−) mice. Female ApoE−/− mice (age: 8–9 weeks, n = 10/group) received western type diet (WTD) or WTD supplemented with rivaroxaban (1.2 mg/g) for 14 weeks. In a second arm, mice received a WTD for 14 weeks, followed by continuation with either WTD or WTD supplemented with rivaroxaban (1.2 mg/g) for 6 weeks (total 20 weeks). Atherosclerotic burden in aortic arch was assessed by haematoxilin & eosin immunohistochemistry (IHC); plaque vulnerability was examined by IHC against macrophages, collagen, vascular smooth muscle cells (VSMC) and matrix metalloproteinases (MMPs). In addition, PAR1 and -2 expressions and their main activators thrombin and FXa in the plaque were determined in the plaque. Administration of rivaroxaban at human therapeutic concentrations reduced the onset of atherosclerosis (−46%, p < 0.05), and promoted a regression of pre-existing plaques in the carotids (−24%, p < 0.001). In addition, the vulnerability of pre-existing plaques was reduced by FXa inhibition as reflected by reduced macrophages (−39.03%, p < 0.05), enhanced collagen deposition (+38.47%, p < 0.05) and diminished necrotic core (−31.39%, p < 0.05). These findings were accompanied with elevated vascular smooth muscle cells and reduced MMPs. Furthermore, expression of PARs and their activators, thrombin and FXa was diminished after rivaroxaban treatment. Pharmacological inhibition of FXa promotes regression of advanced atherosclerotic plaques and enhances plaque stability. These data suggest that inhibition of FXa may be beneficial in prevention and regression of atherosclerosis, possibly mediated through reduced activation of PARs.

Hexane fraction from the ethanolic extract of Sargassum serratifolium suppresses cell adhesion molecules via regulation of NF-\u03baB and Nrf2 pathway in human umbilical vein endothelial cells

Sargassum serratifolium ethanolic extract has been known for strong antioxidant and anti-inflammatory properties. We prepared hexane fraction from the ethanolic extract of S. serratifolium (HSS) to improve biological activities. In this study, we investigated the effects of HSS on the inhibition of tumor necrosis factor (TNF)-α-induced monocyte adhesion to human umbilical vein endothelial cells (HUVECs). We found that HSS suppressed the production of cell adhesion molecules such as intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 in TNF-α-induced HUVECs. Moreover, TNF-α-induced production of monocyte chemoattractant protein 1 and keratinocyte chemoattractant was inhibited by HSS treatment. HSS suppressed TNF-α-induced nuclear factor kappa B (NF-κB) activation via preventing proteolytic degradation of inhibitor κB-α. HSS induced the production of heme oxygenase 1 via translocation of Nrf2 into the nucleus in TNF-α-treated HUVECs. Overall, HSS alleviated vascular inflammation through the downregulation of NF-κB activation and the upregulation of Nrf2 activation in TNF-α-induced HUVECs. These results indicate that HSS may be used as therapeutic agents for vascular inflammatory disorders.

Piezo1 and Gq/G11 promote endothelial inflammation depending on flow pattern and integrin activation.

The vascular endothelium is constantly exposed to mechanical forces, including fluid shear stress exerted by the flowing blood. Endothelial cells can sense different flow patterns and convert the mechanical signal of laminar flow into atheroprotective signals, including eNOS activation, whereas disturbed flow in atheroprone areas induces inflammatory signaling, including NF-κB activation. How endothelial cells distinguish different flow patterns is poorly understood. Here we show that both laminar and disturbed flow activate the same initial pathway involving the mechanosensitive cation channel Piezo1, the purinergic P2Y2 receptor, and Gq/G11-mediated signaling. However, only disturbed flow leads to Piezo1- and Gq/G11-mediated integrin activation resulting in focal adhesion kinase-dependent NF-κB activation. Mice with induced endothelium-specific deficiency of Piezo1 or Gαq/Gα11 show reduced integrin activation, inflammatory signaling, and progression of atherosclerosis in atheroprone areas. Our data identify critical steps in endothelial mechanotransduction, which distinguish flow pattern-dependent activation of atheroprotective and atherogenic endothelial signaling and suggest novel therapeutic strategies to treat inflammatory vascular disorders such as atherosclerosis.