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

Small Vessel Replacement by Human Umbilical Arteries With Polyelectrolyte Film-Treated Arteries In Vivo Behavior

ObjectiveThe aim of this study was to evaluate the patency of human umbilical arteries treated with polyelectrolyte multilayers (PEMs) after rabbit implantation.BackgroundThe development of small-caliber vascular substitutes with high patency after implantation remains a real challenge for vascular tissue engineering.MethodsCryopreserved human umbilical arteries were enzymatically de-endothelialized and the luminal surfaces were coated with poly(styrene sulfonate)/poly(allylamine hydrochloride) (PSS/PAH) multilayers. The PEM-untreated arteries and PEM-treated rabbit carotids were used as graft control. The native rabbit carotids were bypassed by grafts.ResultsThe Doppler ultrasound evaluation, performed in vivo, showed that all PEM-treated grafts remained patent during the full experimental period, whereas after only 1 week, no blood circulation was detected in untreated arteries. Scanning electron microscopy and histological graft examination showed pervasive thrombus formation on the luminal surface of untreated arteries after 1 week and clean luminal surface for treated arteries for at least up to 12 weeks. The arterial wall cells were identified through alpha-smooth muscle actin αυδ platelet endothelial cell adhesion molecule-1 expression. The smooth muscle cells positive to alpha-smooth muscle actin were identified in adventitia and media and the endothelial cells positive to platelet endothelial cell adhesion molecule in intima. Von Kossa reaction didn't reveal any calcium salt deposits on the wall arteries, suggesting a good wall remodelling with no sign of graft rejection.ConclusionsThe in vivo evaluation of human umbilical arteries treated with PSS/PAH multilayers demonstrated a high graft patency after 3 months of implantation. Such modified arteries could constitute a useful option for small vascular replacement

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

Absence of cardiotrophin 1 is associated with decreased age-dependent arterial stiffness and increased longevity in mice

Cardiotrophin 1 (CT-1), an interleukin 6 family member, promotes fibrosis and arterial stiffness. We hypothesized that the absence of CT-1 influences arterial fibrosis and stiffness, senescence, and life span. In senescent 29-month- old mice, vascular function was analyzed by echotracking device. Arterial histomorphology, senescence, metabolic, inflammatory, and oxidative stress parameters were measured by immunohistochemistry, reverse transcription polymerase chain reaction, Western blot, and ELISA. Survival rate of wild-type and CT-1–null mice was studied. Vascular smooth muscle cells were treated with CT-1 (10 −9 mol/L) for 15 days to analyze senescence. The wall stress-incremental elastic modulus curve of old CT-1–null mice was shifted rightward as compared with wild-type mice, indicating decreased arterial stiffness. Media thickness and wall fibrosis were lower in CT-1–null mice. CT-1–null mice showed decreased levels of inflammatory, apoptotic, and senescence pathways, whereas telomere-linked proteins, DNA repair proteins, and antioxidant enzyme activities were increased. CT-1–null mice displayed a 5-month increased median longevity compared with wild-type mice. In vascular smooth muscle cells, chronic CT-1 stimulation upregulated apoptotic and senescence markers and downregulated telomere-linked proteins. The absence of CT-1 is associated with decreased arterial fibrosis, stiffness, and senescence and increased longevity in mice likely through downregulating apoptotic, senescence, and inflammatory pathways. CT-1 may be a major regulator of arterial stiffness with a major impact on the aging proces

Increased atherosclerotic plaque in AOC3 knock-out in ApoE-/- mice and characterization of AOC3 in atherosclerotic human coronary arteries

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, alpha-SMA, and CD3 staining in the plaque independently of a cholesterol modification. At 25 weeks old, advanced plaques were larger with equivalent staining for alpha-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

Cardiotrophin 1 is involved in cardiac, vascular, and renal fibrosis and dysfunction

Cardiotrophin 1 (CT-1), a cytokine belonging to the interleukin 6 family, is increased in hypertension and in heart failure. We aimed to study the precise role of CT-1 on cardiac, vascular, and renal function; morphology; and remodeling in early stages without hypertension. CT-1 (20 g/kg per day) or vehicle was administrated to Wistar rats for 6 weeks. Cardiac and vascular functions were analyzed in vivo using M-mode echocardiography, Doppler, and echo tracking device and ex vivo using a scanning acoustic microscopy method. Cardiovascular and renal histomorphology were measured by immunohistochemistry, RT-PCR, and Western blot. Kidney functional properties were assessed by serum creatinine and neutrophile gelatinase-associated lipocalin and microalbuminuria/creatininuria ratio. Without alterations in blood pressure levels, CT-1 treatment increased left ventricular volumes, reduced fractional shortening and ejection fraction, and induced myocardial dilatation and myocardial fibrosis. In the carotid artery of CT-1–treated rats, the circumferential wall stress-incremental elastic modulus curve was shifted leftward, and the acoustic speed of sound in the aorta was augmented, indicating increased arterial stiffness. Vascular media thickness, collagen, and fibronectin content were increased by CT-1 treatment. CT-1–treated rats presented unaltered serum creatinine concentrations but increased urinary and serum neutrophile gelatinase-associated lipocalin and microalbuminuria/creatininuria ratio. This paralleled a glomerular and tubulointerstitial fibrosis accompanied by renal epithelial-mesenchymal transition. CT-1 is a new potent fibrotic agent in heart, vessels, and kidney able to induce cardiovascular-renal dysfunction independent from blood pressure. Thus, CT-1 could be a new target simultaneously integrating alterations of heart, vessels, and kidney in early stages of heart failure

Covid-19 effects on ARTErial StIffness and vascular AgeiNg: CARTESIAN study rationale and protocol

In December 2019, an outbreak of pneumonia caused by a novel Coronavirus (COVID-19) spread rapidly worldwide. Although the clinical manifestations of COVID-19 are dominated by respiratory symptoms, the cardiovascular system is extensively affected at multiple levels. Due to the unprecedented consequences of the COVID-19 pandemic, the ARTERY society decided to launch the Covid-19 effects on ARTErial StIffness and vascular AgeiNg (CARTESIAN) study — the first international multicentre study into the effects of COVID-19 on non-invasive biomarkers of vascular ageing. The main study objective is to evaluate the presence of Early Vascular Ageing (EVA) 6 and 12 months after COVID-19 infection. Secondary objectives are to study the effect of COVID-19 disease severity on EVA, to investigate the role of psychosocial factors in COVID-19 induced EVA, and to investigate the potential modifying effect of comorbidities and chronic treatments. In the CARTESIAN study, a broad array of cardiovascular measurements, including carotid-femoral pulse wave velocity, central blood pressure, carotid ultrasound, brachial flow-mediated dilatation, will be performed. To date, 43 centres from 21 countries have agreed to participate, with an expected study population of >2500 individuals. To our knowledge, CARTESIAN will be the first study to provide insight into the relationship between COVID-19, its severity, and early vascular ageing in a large cohort, potentially enabling future care and diagnostics to be more focused on the most vulnerable

O2 Level Controls Hematopoietic Circulating Progenitor Cells Differentiation into Endothelial or Smooth Muscle Cells

BACKGROUND:Recent studies showed that progenitor cells could differentiate into mature vascular cells. The main physiological factors implicated in cell differentiation are specific growth factors. We hypothesized that simply by varying the oxygen content, progenitor cells can be differentiated either in mature endothelial cells (ECs) or contractile smooth muscle cells (SMCs) while keeping exactly the same culture medium. METHODOLOGY/PRINCIPAL FINDINGS:Mononuclear cells were isolated by density gradient were cultivated under hypoxic (5% O2) or normoxic (21% O2) environment. Differentiated cells characterization was performed by confocal microscopy examination and flow cytometry analyses. The phenotype stability over a longer time period was also performed. The morphological examination of the confluent obtained cells after several weeks (between 2 and 4 weeks) showed two distinct morphologies: cobblestone shape in normoxia and a spindle like shape in hypoxia. The cell characterization showed that cobblestone cells were positive to ECs markers while spindle like shape cells were positive to contractile SMCs markers. Moreover, after several further amplification (until 3(rd) passage) in hypoxic or normoxic conditions of the previously differentiated SMC, immunofluorescence studies showed that more than 80% cells continued to express SMCs markers whatever the cell environmental culture conditions with a higher contractile markers expression compared to control (aorta SMCs) signature of phenotype stability. CONCLUSION/SIGNIFICANCE:We demonstrate in this paper that in vitro culture of peripheral blood mononuclear cells with specific angiogenic growth factors under hypoxic conditions leads to SMCs differentiation into a contractile phenotype, signature of their physiological state. Moreover after amplification, the differentiated SMC did not reverse and keep their contractile phenotype after the 3rd passage performed under hypoxic and normoxic conditions. These aspects are of the highest importance for tissue engineering strategies. These results highlight also the determinant role of the tissue environment in the differentiation process of vascular progenitor cells

International consensus on the prevention of venous and arterial thrombotic events in patients with inflammatory bowel disease.

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

Influence des conditions de culture sur la différenciation de progéniteurs vasculaires en vue de l'obtention d'un substitut vasculaire autologue

L augmentation de la fréquence des pathologies vasculaires va créer ces prochaines années, des besoins importants en substituts vasculaires de petits calibres. L idéal, à ce jour, reste l utilisation de vaisseaux autologues réduisant les risques infectieux et immunologiques mais d usage limité ce qui est à l origine de l ingénierie cellulaire. L identification des progéniteurs vasculaires est d un intérêt majeur dans ce domaine. Ces cellules d origine autologues sont douées d une grande capacité de prolifération et d un potentiel de différenciation en cellules vasculaires (cellules endothéliales (CE) et cellules musculaires lisses (CML)) mais la difficulté réside dans le choix du recouvrement de la surface du support de culture qui favorise leur adhésion et prolifération Dans ce travail, nous avons choisi les films multicouches de polyélectrolytes et mesuré leur impact sur le comportement de ces cellules progénitrices en fonction de différentes conditions de culture (normoxie ou hypoxie). Nous avons montré dans un premier temps, que ces films multicouches de polyélectrolytes permettaient d accélérer la différenciation de ces cellules en CE matures. Nous avons également montré que ces mêmes cellules cultivées en hypoxie étaient capables de se différencier en cellules contractiles stables dans le temps, présentant un phénotype comparable à celui des CML matures. L association de ces résultats additionnés aux avantages apportés par des feuillets détachables est à la base de la construction d un substitut vasculaire autologue de petit calibre, composé de CE et de CML issues d un même pool de cellules, mais cultivées dans des conditions différentes.The increase of vascular pathologies is going to create these next years, important needs in vascular substitutes of small calibres. The gold standard, this day, remains the use of autologous vessels reducing the infectious and immunological risks, but of limited custom, which is at the origin of tissue engineering. The identification of vascular progenitor cells is of major interest in vascular engineering. These autologous cells present a high capacity of proliferation and a potential of differentiation in vascular cells (endothelial cells (EC) and smooth muscle cells (SMC)) but the difficulty lies in the choice of the coated surface of culture which facilitates their adhesion and proliferation. In this work, we chose polyelectrolytes multilayer films and measured their impact on these vascular progenitor cells in various conditions of culture (normoxia or hypoxia). We showed at first, that these polyelectrolytes multilayer films allowed to accelerate the differentiation of these cells into matures EC. We also showed that these same cells cultivated under hypoxic conditions were able to differentiate into stable and contractile cells, presenting a phenotype comparable to the mature SMC. The association of these results added to the advantages brought by detachable sheet is the basis of the construction of an autologous small calibre vascular substitute consisting of EC and SMC differentiated from the same pool of cells, but cultivated in different conditions.NANCY1-Bib. numérique (543959902) / SudocSudocFranceF