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With advancing age, changes in the arterial wall contribute to what has been called vascular aging, and in some prematurely affected subjects even early vascular aging (EVA).[[1], [2], [3], [4], [5]] Several years ago,[1] we listed various components of EVA, including arteriosclerosis, atherosclerosis, and excess vasoconstriction, with their clinical expression: arterial stiffening and increased central pulse pressure, carotid intima media thickening and endothelial dysfunction, and increased total peripheral resistance, respectively. However, an average vascular aging may not be the desirable goal for patients and their physicians in a population where cardiovascular risk factors are prevalent, and an ideal aging[8] or at least a healthy vascular aging (HVA)[38],[39] would be preferable. The boundaries between early vascular aging (EVA), average vascular aging, healthy vascular aging (HVA), and supernormal vascular aging (SUPERNOVA) are presented as gray zones (Text). Thus, vascular aging based on cardiovascular risk factor may fail at identifying people excessively sensitive (EVA) to or protected against (HVA) risk factors, whereas PWV represents the cumulative damage of all cardiovascular risk factors on the arterial wall. The glucagon-like peptide-1 analog exendin-4 may also contribute to the redox homeostasis by reducing the nucleocytoplasmic shuttling of Nrf2 through its acetylation, thus increasing its transcriptional activity and decreasing VSMC senescence.[68] Localized disturbed blood flow has emerged as a master regulator of the association of Nrf2 with HDAC1/2/3 leading to deacetylation of Nrf2 and sensitizing the endothelium to oxidative stress.[69] Additional potential mechanisms holding off vascular aging and VSMC senescence in NMRs include increased levels of high molecular mass hyaluronan and differentially expressed long noncoding RNAs among which several are coexpressed with HA-related genes.[70]. [Extracted from the article]

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]

The article focuses on the relation between hypertension and arterial stiffness and focuses on the research on Windkessel Model and Aortic Stiffness and the age related changes in the disease.

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]