Vascular smooth muscle cells and arterial stiffening : relevance in development, aging, and disease

The cushioning function of large arteries encompasses distension during systole and recoil during diastole which transforms pulsatile flow into a steady flow in the microcirculation. Arterial stiffness, the inverse of distensibility, has been implicated in various etiologies of chronic common and monogenic cardiovascular diseases and is a major cause of morbidity and mortality globally. The first components that contribute to arterial stiffening are extracellular matrix (ECM) proteins that support the mechanical load, while the second important components are vascular smooth muscle cells (VSMCs), which not only regulate actomyosin interactions for contraction but mediate also mechanotransduction in cell-ECM homeostasis. Eventually, VSMC plasticity and signaling in both conductance and resistance arteries are highly relevant to the physiology of normal and early vascular aging. This review summarizes current concepts of central pressure and tensile pulsatile circumferential stress as key mechanical determinants of arterial wall remodeling, cell-ECM interactions depending mainly on the architecture of cytoskeletal proteins and focal adhesion, the large/small arteries cross-talk that gives rise to target organ damage, and inflammatory pathways leading to calcification or atherosclerosis. We further speculate on the contribution of cellular stiffness along the arterial tree to vascular wall stiffness. In addition, this review provides the latest advances in the identification of gene variants affecting arterial stiffening. Now that important hemodynamic and molecular mechanisms of arterial stiffness have been elucidated, and the complex interplay between ECM, cells, and sensors identified, further research should study their potential to halt or to reverse the development of arterial stiffness

Sex Difference in Cardiovascular Risk Role of Pulse Pressure Amplification

ObjectivesThe study was to explore whether the brachial/carotid pulse pressure (B/C-PP) ratio selectively predicts the sex difference in age-related cardiovascular (CV) death.BackgroundHypertension and CV complications are more severe in men and post-menopausal women than in pre-menopausal women. C-PP is lower than B-PP, and the B/C-PP ratio is a physiological marker of PP amplification between B and C arteries that tends toward 1.0 with age.MethodsThe study involved 72,437 men (ages 41.0 ± 11.1 years) and 52,714 women (39.5 ± 11.6 years). C-PP was calculated for each sex by a multiple regression analysis including B-PP, age, height and risk factors, and a method validated beforehand in a subgroup of 834 subjects. During the 12 years of follow-up, 3,028 men and 969 women died.ResultsIn the total population, the adjusted hazard ratios (HR) (95% confidence interval [CI]) of B/C-PP ratio were: 1) for all-cause mortality: men, HR: 1.51 (95% CI: 1.47 to 1.56), women; HR: 2.46 (95% CI: 2.27 to 2.67) (p < 0.0001); and 2) for CV mortality: men, HR 1.81 (95% CI: 1.70 to 1.93); women, HR: 4.46 (95% CI: 3.66 to 5.45) (p < 0.0001). The B/C-PP impact on mortality did not significantly increase from younger men to those ≥55 years of age, from: HR: 1.44 (95% CI: 1.31 to 1.58) to HR 1.65 (95% CI: 1.48 to 1.84), but increased significantly with age in women: HR: 3.19 (95% CI: 2.08 to 4.89) versus HR: 5.60 (95% CI: 4.17 to 7.50) (p < 0.01). Thus, the mortality impact of B/C-PP ratio was 3-fold higher in women than in men ≥55 years old.ConclusionsPP amplification is highly predictive of differences in CV risk between men and women. In post-menopausal women, the attenuation of PP amplification, mainly related to increased aortic stiffness, contributes to the significant increase in CV risk

Hypercoagulabilité associée aux anticorps anti-phospholipides (approches descriptives et mécanistiques)

L objectif était d identifier le ou le(s) mécanismes contribuant à l hypercoagulabilité associée aux anticorps anti-phospholipides. L activation plaquettaire induite par les anticorps ainsi que l interférence des complexes anticorps/antigène avec les réactions dépendantes des phospholipides ont été étudiées. Des anticorps monoclonaux murins dirigés contre la ß2-glycoproteine I et la prothrombine ont été utilisés comme modèle des anticorps anti-phospholipides. Les résultats obtenus montrent que ces anticorps ont un effet anticoagulant qui se traduit par une diminution de la génération de thrombine et un effet procoagulant qui se traduit par une inhibition de l activité de la protéine C activée. Ces anomalies surviennent indépendamment de l activation plaquettaire. La résultante globale est une hypercoagulabilité. Une activation plaquettaire, suffisamment intense, augmente la quantité de phospholipides procoagulants et neutralise partiellement l effet anticoagulant des anticorps anti-phospholipides. Ainsi, l activation plaquettaire contribue à renforcer l hypercoagulabilité due à la résistance à la protéine C activée. Les complexes anticorps/antigène interfèrent avec les complexes pro- et anticoagulants au niveau des surfaces plaquettaires. Les avidités respectives de chacun des partenaires étudiés pour les surfaces phospholipidiques participent aux mécanismes conduisant à l'hypercoagulabilité associée aux anticorps anti-phospholipides.The objective was to identify the mechanisms which contribute to the hypercoagulability associated with anti-phospholipid antibodies. Antibody-mediated platelet activation and interference of antibodies with phospholipid-dependent reactions were investigated. Murine monoclonal antibodies directed against ß2-glycoprotein I and prothrombin were used as model of anti-phospholipid antibodies. An anticoagulant effect, evidenced by impairment of thrombin generation and a procoagulant effect, by inhibition of activated protein C activity were shown. These phenomena occurs independently of platelet activation. The overall result was hypercoagulability. When immune-mediated platelet activation is sufficiently intense, it increases the amount of procoagulant phospholipids and antagonizes partially the anticoagulant effect of anti-phospholipid antibodies. Thus platelet activation contributes to reinforce the hypercoagulability due to activated protein C resistance. The antibody/antigen complexes interfere with pro- and anticoagulant complexes to the platelet surfaces. The avidity of each studied partners for the phospholipid surfaces take part in the mechanisms leading to hypercoagulability associated with antiphospholipid antibodies.NANCY1-Bib. numérique (543959902) / SudocSudocFranceF

Sirtuin 1 steers anti-inflammatory effects in vascular smooth muscle cells: protection without burden?

International audienc

Caractérisation des propriétés pro- et anti-coagulantes associées aux cellules musculaires lisses vasculaires

L'objectif principal de ce travail était de comparer l'implication (i) de cellules vasculaires, cellules musculaires lisses vasculaires (CML) et cellules endothéliales (CE), ou des cellules circulantes, les plaquettes, et (ii) des microparticules (MP) issues de ces différentes cellules dans la génération de la thrombine mais également dans son inhibition par les systèmes anticoagulants de la protéine C activée (PCa) et de l'inhibiteur de la voie du facteur tissulaire (TFPI), et d'identifier les mécanismes et les déterminants responsables des différences observées entre ces supports cellulaires pour la coagulation. Nous avons démontré que l'intégrine [alpha]v[gamma]3 qui est le récepteur pour la prothrombine sur les surfaces vasculaires était impliquée dans la génération de thrombine à la surface des CML soumises ou non à des déformations mécaniques cycliques. A l'état de base, les CML et les CE ont un potentiel thrombinique similaire, mais moins important que celui des plaquettes. Nous avons montré un rôle synergique du TFPI avec la PCa dans l'inhibition de la génération de thrombine à la surface de ces cellules plus importante avec les CML qu'avec les CE. L'ensemble de nos résultats suggère que les CML pourraient exercer des effets procoagulants comparables aux CE mais avec des régulations différentes en réponse aux facteurs pro- et anticoagulants, et que les MP issues de cellules vasculaires ont un pouvoir thrombogène très supérieur à leurs cellules d'origineThe main objective of this study was to compare the implication (i) of vascular cells, smooth muscle cells (SMC) and endothelial cells (EC), or circulating cells, platelets, and (ii) microparticles (MP) derived from these different cells in the generation of thrombin but also in its inhibition by the activated protein C (APC) and the tissue factor pathway inhibitor (TFPI), and to identify the mechanisms and determinants responsibles for observed differences between these different cell supports for coagulation. We have demonstrated that [alpha]v[gamma]3 integrin, the prothrombin receptor on the vascular surfaces, was involved in the generation of thrombin on the surface of these cells subjected or not subjected to cyclic mechanical deformations. At baseline, SMC and EC, have equivalent thrombin generating capacities, but less than that of platelets. We have shown a synergistic role of TFPI with APC in the inhibition of thrombin generation at the surface of these cells, more important with SMC than with EC. Taken together, our results suggest that SMC may exert procoagulant effects comparable to EC but with different regulations in response to pro-and anticoagulant factors, and that MP derived from vascular cells have a very higher thrombogenic activity compared to their parent cellsMETZ-SCD (574632105) / SudocNANCY1-Bib. numérique (543959902) / SudocNANCY2-Bibliotheque electronique (543959901) / SudocNANCY-INPL-Bib. électronique (545479901) / SudocSudocFranceF

Changements hémostatiques du syndrome métabolique, de l'hypertension artérielle, et de l'insuffisance cardiaque (approches physiologique et physiopathologique)

L'allongement de l'espérance de vie a fait de l'insuffisance cardiaque (IC) l'un des problèmes majeurs de santé publique. Le syndrome métabolique (SMet) et l'hypertension sont deux facteurs conduisant à l'IC. Les modifications qui interviennent au niveau structural et cellulaire de la paroi artérielle dans le SMet, l'hypertension et l'IC pourraient entraîner des anomalies de l'hémostase qui aggravent ces tableaux cliniques. Nous avons montré au cour de ce travail les modifications du phénotype de l'hémostase dans différents modèles animaux de pathologies impliquées dans la mise en place de l'IC. L'altération de l'hémostase précède les modifications de la paroi et pourrait favoriser le développement de l'IC chez le rat Zucker. Le modèle de rat spontanément hypertendu SHR présente une hypercoagulablité de la paroi via les cellules musculaires lisses. Ces résultats ne permettent pas d'impliquer uniquement l'hypertension artérielle dans l'hypercoagulabilité plasmatique trouvée chez le rat Zucker. L'activation du récepteur à l'aldsotérone au niveau endothélial chez la souris induit un phénotype antithrombotique provoqué par une augmentation de la réactivité du système anticoagulant de la protéine C, via son récepteur, l'EPCR. L'étude d'une cohorte de patients insuffisants cardiaques a permis de distinguer des paramètres de fonction cardiaque et de rigidité artérielle. Cette caractérisation est indispensable pour comprendre les mécanismes des événements thrombotiques associés à l'IC. La conclusion de ce travail est que les pathologies pouvant conduire à la mise en place d'une IC modifient l'hémostase vers un état d'hypercoagulabilité qui fait intervenir la paroi artérielleIncreasing life span has made heart failure (HF) a major issue for public health. The metabolic syndrome (MetS) and hypertension are two important factors which can lead to HF. Structural and cellular modification occurring in the arterial wall in the MetS, hypertension and HF may provoke hemostasis alterations that can worsen the clinical situation. We have shown in this work, hemostasis modifications in animal models of pathologies implicated in HF development. Hemostasis alterations were shown to precede functional modifications of the arterial wall and could favor HF development in Zucker rats. Spontaneously hypertensive rats showed an arterial wall hypercoagulability via smooth muscle cells. These results don't permit the implication of hypertension in the hypercoagulable state found in the Zucker rat. A mouse model with aldosterone receptor activation in the endothelium lead to a hypocoagulable state by increasing the protein C anticoagulant system via his receptor, the EPCR. Studying a human HF patient cohort permitted the measurement of cardiac function and of arterial stiffness parameters. This characterization is important to understand thrombosis events associated with HF in humans. The general conclusion of this work is that, in pathologies leading to HF, modification of hemostasis to a procoagulable state, implicates the arterial wallMETZ-SCD (574632105) / SudocNANCY1-Bib. numérique (543959902) / SudocNANCY2-Bibliotheque electronique (543959901) / SudocNANCY-INPL-Bib. électronique (545479901) / SudocSudocFranceF

Mechanisms of Arterial Stiffening: From Mechanotransduction to Epigenetics

International audienceArterial stiffness is a major independent risk factor for cardiovascular complications causing isolated systolic hypertension and increased pulse pressure in the microvasculature of target organs. Stiffening of the arterial wall is determined by common mechanisms including reduced elastin/collagen ratio, production of elastin cross-linking, reactive oxygen species–induced inflammation, calcification, vascular smooth muscle cell stiffness, and endothelial dysfunction. This brief review will discuss current biological mechanisms by which other cardiovascular risk factors (eg, aging, hypertension, diabetes mellitus, and chronic kidney disease) cause arterial stiffness, with a particular focus on recent advances regarding nuclear mechanotransduction, mitochondrial oxidative stress, metabolism and dyslipidemia, genome mutations, and epigenetics. Targeting these different molecular pathways at different time of cardiovascular risk factor exposure may be a novel approach for discovering drugs to reduce arterial stiffening without affecting artery strength and normal remodeling

Sex Differences in Arterial Stiffening and Central Pulse Pressure: Mechanistic Insights?

International audienc

Liraglutide and Renal Outcomes in Type 2 Diabetes

International audienc

Étude de l'implication des cellules musculaires lisses vasculaires dans la distensibilité et le phénotype thrombotique dans des modèles murins

L'hypothèse que l'hypertension peut conférer un état d'hypercoagulabilité découle des principales complications liées à l'hypertension, l'infarctus du myocarde et accident vasculaire cérébral. Notre objectif était de déterminer si l'hypertension spontanée confère des changements dans les protéines de la coagulation et de la capacité de production de thrombine dans le sang et la paroi vasculaire. Nous avons utilisé le modèle de rats spontanément hypertendus (SHR) par rapport aux rats Wistar. La génération de thrombine est plus faible dans le plasma riche en plaquettes et plasma sans plaquettes de SHR par rapport à Wistar. Ceci est lié aux faibles concentrations en facteur tissulaire (TF) et en prothrombine, ainsi qu'un taux plus élevé de TFPI dans le plasma des SHR. En revanche, l'ajout d'anneaux d'aorte thoracique de SHR à un pool de plasma Wistar a donné lieu à une augmentation plus importante dans la génération de thrombine par rapport à l'ajout d'anneaux équivalent du Wistar. Alors qu'aucune différence n'a été observée pour les cellules endothéliales, la formation de thrombine était plus élevée à la surface de culture CML aortiques des SHR que des Wistar. L'exposition des phospholipides chargés négativement est plus élevée sur les anneaux et les CML des SHR que les Wistar. Les activités TF et TFPI étaient plus élevés chez les CML des SHR. Ces résultats montrent une opposition de génération de thrombine à la surface de la paroi artérielle et dans le plasma des rats SHR par rapport aux rats Wistar. Le phénotype thrombotique plus élevé de la paroi vasculaire SHR est dû à la capacité du CML à soutenir la génération de thrombine. Ces résultats suggèrent que le remodelage de la membrane phospholipidique et la synthèse de molécules pro-coagulantes induites par hypertension dans les CML sont des substrats pour une formation de thrombine accrue dans la paroi vasculaireThe hypothesis that hypertension may confer a hypercoagulable state arises from the main complications associated with hypertension, stroke and myocardial infarction. Our objective was to determine whether spontaneous hypertension confers changes in the coagulation proteins and the thrombin generating capacity in blood and the vascular wall. We used the model of spontaneously hypertensive rats (SHR) compared with Wistar rats. Thrombin generation was lower in platelet-rich plasma and platelet-free plasma from SHR compared to Wistar. This was related to lower tissue factor (TF) and prothrombin as well as higher TFPI levels in SHR plasma. In contrast, the addition of thoracic aorta rings of SHR to a Wistar plasma pool resulted in a higher increase in thrombin generation compared to the addition of equivalent rings from Wistar. Whereas no difference was observed for endothelial cells, thrombin formation was higher at the surface of cultured SHR aortic SMCs than from Wistar. Exposure of negatively-charged phospholipids was higher on SHR than on Wistar rings as well as on SMCs. TF and TFPI activities were higher in SHR SMCs. These results show opposite thrombin generating capacity of plasma and vessel walls in SHR compared to Wistar. The higher prothrombotic phenotype of the SHR vessel wall was due to the ability of SMCs to support thrombin generation. These findings suggest that the hypertension-induced membrane phospholipid reorganization and synthesis of procoagulant molecules in SMCs provide substrates for increased thrombin formation within the vessel wallMETZ-SCD (574632105) / SudocNANCY1-Bib. numérique (543959902) / SudocNANCY2-Bibliotheque electronique (543959901) / SudocNANCY-INPL-Bib. électronique (545479901) / SudocSudocFranceF