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Bone diseases are increasing with aging populations and it is important to identify clues to develop innovative treatments. Vasn, which encodes vasorin (Vasn), a transmembrane protein involved in the pathophysiology of several organs, is expressed during the development in intramembranous and endochondral ossification zones. Here, we studied the impact of Vasn deletion on the osteoblast and osteoclast dialog through a cell Coculture model. In addition, we explored the bone phenotype of Vasn KO mice, either constitutive or tamoxifen‐inducible, or with an osteoclast‐specific deletion. First, we show that both osteoblasts and osteoclasts express Vasn. Second, we report that, in both KO mouse models but not in osteoclast‐targeted KO mice, Vasn deficiency was associated with an osteopenic bone phenotype, due to an imbalance in favor of osteoclastic resorption. Finally, through the Coculture experiments, we identify a dysregulation of the Wnt/β‐catenin pathway together with an increase in RANKL release by osteoblasts, which led to an enhanced osteoclast activity. This study unravels a direct role of Vasn in bone turnover, introducing a new biomarker or potential therapeutic target for bone pathologies. [ABSTRACT FROM AUTHOR]

Within the cardiovascular system, the protein vasorin (Vasn) is predominantly expressed by vascular smooth muscle cells (VSMCs) in the coronary arteries and the aorta. Vasn knockout (Vasn−/−) mice die within 3 weeks of birth. In the present study, we investigated the role of vascular Vasn expression on vascular function. We used inducible Vasn knockout mice (VasnCRE‐ERT KO and VasnSMMHC‐CRE‐ERT2 KO, in which respectively all cells or SMCs only are targeted) to analyze the consequences of total or selective Vasn loss on vascular function. Furthermore, in vivo effects were investigated in vitro using human VSMCs. The death of VasnCRE‐ERT KO mice 21 days after tamoxifen injection was concomitant with decreases in blood pressure, angiotensin II levels, and vessel contractibility to phenylephrine. The VasnSMMHC‐CRE‐ERT2 KO mice displayed concomitant changes in vessel contractibility in response to phenylephrine and angiotensin II levels. In vitro, VASN deficiency was associated with a shift toward the SMC contractile phenotype, an increase in basal intracellular Ca2+ levels, and a decrease in the SMCs' ability to generate a calcium signal in response to carbachol or phenylephrine. Additionally, impaired endothelium‐dependent relaxation (due to changes in nitric oxide signaling) was observed in all Vasn knockout mice models. Our present findings highlight the role played by Vasn SMC expression in the maintenance of vascular functions. The mechanistic experiments suggested that these effects are mediated by SMC phenotype switching and changes in intracellular calcium homeostasis, angiotensin II levels, and NO signaling. [ABSTRACT FROM AUTHOR]

The endothelium has a fundamental role in the cardiovascular complications of coronavirus disease 2019 (COVID-19). Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) particularly affects endothelial cells. The virus binds to the angiotensin-converting enzyme 2 (ACE-2) receptor (present on type 2 alveolar cells, bronchial epithelial cells, and endothelial cells), and induces a cytokine storm. The cytokines tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 have particular effects on endothelial cells—leading to endothelial dysfunction, endothelial cell death, changes in tight junctions, and vascular hyperpermeability. Under normal conditions, apoptotic endothelial cells are removed into the bloodstream. During COVID-19, however, endothelial cells are detached more rapidly, and do not regenerate as effectively as usual. The loss of the endothelium on the luminal surface abolishes all of the vascular responses mediated by the endothelium and nitric oxide production in particular, which results in greater contractility. Moreover, circulating endothelial cells infected with SARS-CoV-2 act as vectors for viral dissemination by forming clusters that migrate into the circulation and reach distant organs. The cell clusters and the endothelial dysfunction might contribute to the various thromboembolic pathologies observed in COVID-19 by inducing the formation of intravascular microthrombi, as well as by triggering disseminated intravascular coagulation. Here, we review the contributions of endotheliopathy and endothelial-cell-derived extracellular vesicles to the pathogenesis of COVID-19, and discuss therapeutic strategies that target the endothelium in patients with COVID-19. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a frequent disease encountered in the hospital, with a higher incidence in intensive care units. Despite progress in renal replacement therapy, AKI is still associated with early and late complications, especially cardiovascular events and mortality. The role of gut-derived protein-bound uremic toxins (PBUTs) in vascular and cardiac dysfunction has been extensively studied during chronic kidney disease (CKD), in particular, that of indoxyl sulfate (IS), para-cresyl sulfate (PCS), and indole-3-acetic acid (IAA), resulting in both experimental and clinical evidence. PBUTs, which accumulate when the excretory function of the kidneys is impaired, have a deleterious effect on and cause damage to cardiovascular tissues. However, the link between PBUTs and the cardiovascular complications of AKI and the pathophysiological mechanisms potentially involved are unclear. This review aims to summarize available data concerning the participation of PBUTs in the early and late cardiovascular complications of AKI. [ABSTRACT FROM AUTHOR]

Aortic stenosis can cause excessive bleeding by damaging proteins involved in blood clotting, according to a study of 50 patients. In patients with aortic valve stenosis, the aortic valve in the heart is narrower than normal. This damages a large blood clotting protein called von Willebrand factor as it passes through the valve and this in turn causes excessive bleeding. This explains why blood clotting returns to normal in many patients who have the valve replaced with an artificial valve.

Background Vascular calcification (VC) is amplified during chronic kidney disease, partly due to uraemic toxins such as inorganic phosphate (Pi) and indoxyl sulphate (IS) that trigger osteogenic differentiation of vascular smooth muscle cells (VSMCs). These toxins also alter endothelial cell (EC) functions but whether this contributes to VC is unknown. Here, we hypothesized that ECs exposed to Pi and IS promote VSMC calcification. Methods Human umbilical vein ECs were treated with Pi, IS or both, and then the conditioned media [endothelial cell conditioned medium (EC-CM)] was collected. Human aortic SMCs (HASMCs) were exposed to the same toxins, with or without EC-CM, and then calcification and osteogenic differentiation were evaluated. Procalcifying factors secreted from ECs in response to Pi and IS were screened. Rat aortic rings were isolated to assess Pi+IS-induced calcification at the tissue level. Results Pi and Pi+IS induced HASMCs calcification, which was significantly exacerbated by EC-CM. Pi+IS induced the expression and secretion of interleukin-8 (IL-8) from ECs. While IL-8 treatment of HASMCs stimulated the Pi+IS-induced calcification in a concentration-dependent manner, IL-8 neutralizing antibody, IL-8 receptors antagonist or silencing IL-8 gene expression in ECs before collecting EC-CM significantly prevented the EC-CM procalcifying effect. IL-8 did not promote the Pi+IS-induced osteogenic differentiation of HASMCs but prevented the induction of osteopontin (OPN), a potent calcification inhibitor. In rat aortic rings, IS also promoted Pi-induced calcification and stimulated the expression of IL-8 homologues. Interestingly, in the Pi+IS condition, IL-8 receptor antagonist lifted the inhibition of OPN expression and partially prevented aortic calcification. Conclusion These results highlight a novel role of IL-8, whose contribution to VC in the uraemic state results at least from interaction between ECs and VSMCs. [ABSTRACT FROM AUTHOR]

Résumé Le rétrécissement aortique calcifié (RAC) est une pathologie à forte prévalence, caractérisée par un remaniement progressif de la valve aortique avec des conséquences dévastatrices sur le fonctionnement myocardique. Il n’existe pas à l’heure actuelle de traitements capables de ralentir la progression du RAC et le seul geste thérapeutique possible est le remplacement valvulaire par voie chirurgicale ou percutanée (TAVI), proposé à un stade avancé de la maladie, lorsque les symptômes sont présents. Le diagnostic et le suivi de la maladie reposent aujourd’hui essentiellement sur l’imagerie cardiaque. Le développement et l’utilisation de nouveaux marqueurs biologiques pourraient représenter une approche complémentaire. À chaque étape dans l’évolution de la pathologie, des molécules sont libérées dans la circulation dont le dosage constituera des marqueurs capables de refléter d’une part l’atteinte valvulaire et d’autre part les conséquences myocardiques du RAC. La mesure de ces marqueurs circulants, capables d’évaluer la sévérité, la progression et le pronostic du RAC, pourrait être très utile au clinicien en lui fournissant d’une part des renseignements sur l’étiologie et les causes possibles de l’atteinte valvulaire et d’autre part en permettant de stratifier le risque cardiovasculaire global du patient. Ils pourraient in fine , améliorer la prise en charge de la pathologie, en permettant de poser l’indication d’un remplacement valvulaire plus précocement chez les patients asymptomatiques. L’objectif de cette revue est de faire le point sur les principaux marqueurs biologiques qui ont été étudiés dans le RAC en insistant sur ceux qui présentent le plus grand intérêt. Summary Calcified aortic valve disease (CAVD) is a highly prevalent cardiovascular disorder, characterized by a progressive thickening and calcification of the aortic valve with devastating consequences on myocardial function. So far, there are no medical therapies to prevent the progression of CAVD and aortic valve replacement, either surgically or percutaneously, remains the only treatment available in patients with severe symptomatic CAVD. Diagnosis and management of CAVD is generally established using an echocardiographic examination. The development and the use of established or novel biomarkers could represent a complementary approach. During the progression of CAVD, several molecules are released into the circulation whose measurement could reflect either the aortic valve lesions or the myocardium consequences of CAVD. These biomarkers, by giving informations on the severity, the progression and the prognostic of CAVD, would enhance the clinical decision making. They have the advantage over echocardiography examination to provide insight into etiological and causal factors for the disease. Since they can help to stratify the cardiovascular risk, the use of biomarkers would improve the decision to the optimal timing for aortic valve replacement in asymptomatic patients. The objective of this review is to summarize the main biomarkers that have been studied in CAVD and to identify those which have the greatest clinical utility. [ABSTRACT FROM AUTHOR]

Résumé Le rétrécissement aortique calcifié (RAC) est une pathologie cardiovasculaire très fréquente. Elle consiste en un remaniement fibro-calcique de la valve aortique, qui entraîne une insuffisance valvulaire majeure. Dès l’apparition des symptômes tels que dyspnée ou angor et sans une prise en charge rapide, la survie du patient est fortement diminuée. Les mécanismes physiopathologiques de mise en place du rétrécissement aortique calcifié restent encore mal connus, bien que de récentes avancées aient été menées dans ce domaine. Cet article se propose d’explorer dans un premier temps l’histologie et la physiologie cellulaire des valves, puis dans un second temps de s’intéresser aux mécanismes moléculaires mis en place dans la physiopathologie du RAC afin de comprendre quelle est l’origine de la maladie et comment agir sur son évolution. Summary Calcified Aortic Valve Disease (CAVD) is a common cardiovascular disease. It consists in a fibrotic and calcified rearrangement of the aortic valve, which leads to major valvular insufficiency. From the onset of symptoms (as dyspnea or angina), and without prompt management, patient survival is dramatically diminished. Pathophysiological mechanisms of aortic stenosis are little known, although many advances in this area have been done. Our review aims to explore the histology and physiology of the valves, and then, focuses on molecular and cellular mechanisms involved in the origin of the disease. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is characterized by vascular remodeling and the retention of uremic toxins, several of which are independently associated with the high cardiovascular mortality rate in CKD patients. Whether the association between these uremic toxins and cardiovascular mortality is due to induction of vascular dysfunction and resulting vascular remodeling remains to be determined. This study evaluates the effects of para-cresyl sulfate (PCS), a newly identified uremic toxin, on vascular function and remodeling. PCS acutely induced oxidative stress in both endothelial and vascular smooth muscle cells, with a maximal effect at 0.15 mM, corresponding to the mean 'uremic' concentration found in dialysis patients. PCS significantly increased within 30 min phenylephrine-induced contraction of mouse thoracic aorta, through direct activation of rho-kinase, independently of oxidative stress induction, as demonstrated by the capacity of rho-kinase inhibitor Y-27632 to abolish this effect. After exposure of the aorta to PCS for 48 h, we observed inward eutrophic remodeling, a hallmark of uremic vasculopathy characterized by a reduction of the area of both lumen and media, with unchanged media/lumen ratio. In conclusion, elevated PCS concentrations such as those observed in CKD patients, by promoting both vascular dysfunction and vascular remodeling, may contribute to the development of hypertension and to cardiovascular mortality in CKD. J. Cell. Physiol. 230: 2927-2935, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is regarded as a state of Klotho deficiency and FGF23 excess. In patients with CKD a strong association has been found between increased serum FGF23 and mortality risk, possibly via enhanced atherosclerosis, vascular stiffness, and vascular calcification. The aim of this study was to examine the hypothesis that soluble Klotho and FGF23 exert direct, rapid effects on the vessel wall. We used three in vitro models: mouse aorta rings, human umbilical vein endothelial cells, and human vascular smooth muscle cells (HVSMC). Increasing medium concentrations of soluble Klotho and FGF23 both stimulated aorta contractions and increased ROS production in HVSMC. Klotho partially reverted FGF23 induced vasoconstriction, induced relaxation on phosphate preconstricted aorta and enhanced endothelial NO production in HUVEC. Thus Klotho increased both ROS production in HVSMC and NO production in endothelium. FGF23 induced contraction in phosphate preconstricted vessels and increased ROS production. Phosphate, Klotho and FGF23 together induced no change in vascular tone despite increased ROS production. Moreover, the three compounds combined inhibited relaxation despite increased NO production, probably owing to the concomitant increase in ROS production. In conclusion, although phosphate, soluble Klotho and FGF23 separately stimulate aorta contraction, Klotho mitigates the effects of phosphate and FGF23 on contractility via increased NO production, thereby protecting the vessel to some extent against potentially noxious effects of high phosphate or FGF23 concentrations. This novel observation is in line with the theory that Klotho deficiency is deleterious whereas Klotho sufficiency is protective against the negative effects of phosphate and FGF23 which are additive. [ABSTRACT FROM AUTHOR]

Elevated serum phosphate and fibroblast growth factor 23 (FGF23) levels are associated with cardiovascular disease (CVD) in patients with chronic renal failure (CRF). The phosphate-binder sevelamer has been shown to decrease both phosphate and FGF23, but limited data indicate that sevelamer improves CRF-related CVD, such as diastolic dysfunction, left ventricular hypertrophy (LVH), and aortic stiffness. To gain additional information, we measured the effects of sevelamer on CVD in a murine model of CRF. Groups of CRF and sham-operated mice received regular chow or 3% sevelamer-HCl in the chow for 14 weeks, starting 6 weeks after the initiation of CRF or sham operation. After the first 8 weeks of sevelamer treatment, CRF mice had decreased serum phosphate levels and an improved aortic systolic expansion rate, pulse-wave velocity, and diastolic function, although LVH remained unchanged. Following an additional 6-week course of sevelamer, LVH had not progressed. The FGF23 serum level was not reduced by sevelamer until after 14 weeks of treatment. In multiple regression analysis, serum phosphate, but not FGF23, was independently correlated with LV diastolic function and mass. Thus, sevelamer first improved aortic stiffness and diastolic dysfunction and secondarily prevented LVH in mice with CRF. The phosphate-lowering, rather than FGF23-lowering, effect appears to be responsible for the observed cardiovascular improvement. [ABSTRACT FROM AUTHOR]

Objectives: The role of basic fibroblast growth factor (bFGF) in atheroselerotic plaque formation is incompletely understood. Although it may act as a proatherogenic factor clue to its stimulatory effect on smooth muscle cell growth. previous studies have suggested that it may also have beneficial effects by reversing endothelial dysfunction in experimental models. Our purpose was to evaluate the effects of systemic chronic administration of basic FGF on the development or atheroselerotic plaques in a rabbit model. Method: We investigated the effect of bFGF or placebo (2.5 μg IV twice a week), begun on the same day as a cholesterol (2%) diet, and continued For 5 or 10 weeks, on in vitro reactivity, vascular cell adhesion molecule 1 (VCAM- 1) expression and plaque development (protocol 1; n - 37). The effects of bFGF or placebo (2.5 μg IV once a week) were also studied in animals fed a 0.2% cholesterol diet and sacrificed at 3 months (protocol 2; n - 18). Results were compared to those of rabbits fed with a normal chow (normal animals). Results: In protocol I. bFGF administration for 5 week was associated with an improvement in endothelial function (p < 0.05). with a decrease in VCAM- I expression (p = 0.03) and in the macrophage content of the plaque (p = O.02. This preventive effect was lost at 10 weeks. In protocol 2, bFGF was associated with similar "beneficial" endpoints as observed at 5 weeks in protocol 1. Conclusion: Administration of bFGF is associated with important beneficial structural and functional effects in the early stage of experimental atherosclerosis. These results may help us to understand the role of growth factors in atherosclerosis and to anticipate their effects in human arteries. [ABSTRACT FROM AUTHOR]

Proposes that a peroxisome proliferator-activated receptor activator, fenofibrate, protects against cerebral injury by anti-oxidant and anti-inflammatory mechanisms. Neuroprotective effect appears independently of any improvement in plasma lipids or glycemia; Cerebral blood flow measurement; Effect of chronic fenofibrate treatment on sensitivity to endothelial relaxation.

Objective: Growth regulatory properties of nitric oxide (NO) in cultured endothelial cells is controversial. The aim of our study was to investigate the effect of l-arginine, the endogenous NO precursor, and l-NAME, an inhibitor of NO synthase on the reendothelialization process after angioplasty. Methods: Fifty-five New Zealand White rabbits underwent denudation of the left iliac artery. After injury the rabbits were randomized in three groups: l-arginine 2.25% (l-arginine, n=19); NG-nitro-l-arginine methyl ester 15 mg/kg/day (l-NAME, n=19); and placebo (controls, n=17). Treatment was solubilized in drinking water. Reendothelialization was evaluated at 4 weeks by macroscopic evaluation of Evans blue staining and endothelial-specific immunostaining (CD-31) on cross sections. Intimal hyperplasia was evaluated by morphometric analysis. Results: Despite a significant increase in plasma arginine (P=0.001) and a reduction in intimal hyperplasia (P=0.003) with l-arginine, neither agent had a significant effect on reendothelialization at 4 weeks (controls=36±4%, l-arginine=43±3%, l-NAME=33±4%; NS). Conclusion: These results suggest that, in spite of previously demonstrated effects on neointimal hyperplasia, the NO pathway does not influence the regrowth of macrovascular endothelial cells in vivo. [ABSTRACT FROM PUBLISHER]

This study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes endothelium-derived epoxyeicosatrienoic acids, plays a role in vascular calcification. The sEH inhibitor trans-4-(4-(3-adamantan-1-yl-ureido)-cyclohexyloxy)-benzoic acid (t-AUCB) potentiated the increase in calcium deposition of rat aortic rings cultured in high-phosphate conditions. This was associated with increased tissue-nonspecific alkaline phosphatase activity and mRNA expression level of the osteochondrogenic marker Runx2. The procalcifying effect of t-AUCB was prevented by mechanical aortic deendothelialization or inhibition of the production and action of epoxyeicosatrienoic acids using the cytochrome P450 inhibitor fluconazole and the antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE), respectively. Similarly, exogenous epoxyeicosatrienoic acids potentiated the calcification of rat aortic rings through a protein kinase A (PKA)-dependent mechanism and of human aortic vascular smooth muscle cells when sEH was inhibited by t-AUCB. Finally, a global gene expression profiling analysis revealed that the mRNA expression level of sEH was decreased in human carotid calcified plaques compared to adjacent lesion-free sites and was inversely correlated with Runx2 expression. These results show that sEH hydrolase plays a protective role against vascular calcification by reducing the bioavailability of epoxyeicosatrienoic acids. [ABSTRACT FROM AUTHOR]

Vascular dysfunction is an essential element found in many cardiovascular pathologies and in pathologies that have a cardiovascular impact such as chronic kidney disease (CKD). Alteration of vasomotricity is due to an imbalance between the production of relaxing and contracting factors. In addition to becoming a determining factor in pathophysiological alterations, vascular dysfunction constitutes the first step in the development of atherosclerosis plaques or vascular calcifications. In patients with CKD, alteration of vasomotricity tends to emerge as being a new, less conventional, risk factor. CKD is characterized by the accumulation of uremic toxins (UTs) such as phosphate, para-cresyl sulfate, indoxyl sulfate, and FGF23 and, consequently, the deleterious role of UTs on vascular dysfunction has been explored. This accumulation of UTs is associated with systemic alterations including inflammation, oxidative stress, and the decrease of nitric oxide production. The present review proposes to summarize our current knowledge of the mechanisms by which UTs induce vascular dysfunction. [ABSTRACT FROM AUTHOR]

VEGF is an endothelial cell cytokine that promotes angiogenesis and enhances microvascular permeability. Recently, it has been shown that the protein kinase Akt functions in a key intercellular signaling pathway downstream of VEGF. Here, we employed adenovirus-mediated gene transfer in conjunction with the Miles assay in hairless albino guinea pigs to assess the role of Akt signaling in vascular permeability. VEGF-induced vascular permeability was blocked by the transduction of a dominant negative mutant of Akt. Conversely, transduction of a constitutively active form of Akt promoted vascular permeability in a manner similar to VEGF protein administration. This Akt-mediated increase in vascular permeability was inhibited by the eNOS inhibitor L-NAME. These data show that Akt signaling is both necessary and sufficient for vascular permeability in an in vivo model. [Copyright &y& Elsevier]

Little is known about the effects of human free apolipoprotein A-I (Free-Apo A-I) and pre-beta-high density lipoprotein (pre-beta-HDL) on the endothelium function. In this study, we have investigated the effects of Free-Apo A-I and artificial pre-beta-HDL on endothelial NO synthase (eNOS) activity and on NO production by endothelial cells. Free-Apo A-I drastically inhibited NO production in human umbilical cord vein endothelial cells (HUVECs) and eNOS activity in bovine aortic endothelial cells (BAECs). Pre-beta-HDL and serum from human apolipoprotein A-I transgenic rabbits inhibited eNOS activity in BAECs but HDL3 did not. Free-Apo A-I displaced eNOS from BAEC plasma membrane towards intracellular pools without affecting eNOS activity and eNOS mass in BAEC crude homogenates. Free-Apo A-I and HDL3 did not decrease either caveolin bound to BAEC plasma membrane or caveola cholesterol content. As previously described, we showed that HDL3 directly induced endothelium-dependent relaxation of rings from rat aorta. We observed that pre-beta-HDL significantly decreased endothelium-dependent relaxation of rat aortic rings ex vivo. [Copyright &y& Elsevier]