Littérature scientifique sur le sujet « Intraplaque neovascularization »

Neovascularization of a carotid atherosclerotic plaque (AP) is associated with an increased risk of stroke. Contrast-enhanced ultrasonography (CEUS) is a widely used method for imaging intraplaque neovascularization in vivo. Unfortunately, there are no standardized guidelines for CEUS interpretation. The aim of this study was to identify the most reliable method for CEUS-based assessment of AP neovascularization. Seventy-eight AP were removed during carotid endarterectomy in 73 patients, of whom 5 had AP on both sides, and examined morphologically. All patients underwent preoperative duplex scanning and CEUS; Sonovue was used as a contrast agent. AP neovascularization was assessed on a 4-grade visual scale and with 3 different quantitative methods using QLAB software. On the visual scale (method 1), poorly (37%) and moderately (51%) vascularized plaques were the most common. Quantitative analysis (data were presented as Me (Q1; Q3)) revealed that the number of blood vessels per 1 cm2 of the plaque (method 2) was 16 (10; 26), the ratio of the total vessel area to the plaque area (method 3) was 6% (3; 9), and AP ROI (method 4) was 2.6 dB (1.8; 4.1). Significant correlations were demonstrated between the results produced by method 2 and method 3 (р < 0.0001), method 3 and method 2 (p = 0.0006), and between pathomorphological findings and the results produced by methods 1–3, especially method 2 (p < 0.004). AP ROI brightness did not correlate with other results. The presence of hyperechoic components (calcifications) in AP dramatically reduced the reliability of US-based intraplaque neovascularization assessment. The most accurate CEUS-based quantitative method for assessing intraplaque neovascularization is estimation of blood vessel number per 1 cm2 of the plaque.

Objective: Intraplaque neovascularization is an important feature of unstable human atherosclerotic plaques. However, its impact on plaque formation and stability is poorly studied. Because proliferating endothelial cells generate up to 85% of their ATP from glycolysis, we investigated whether pharmacological inhibition of glycolytic flux by the small-molecule 3PO (3-[3-pyridinyl]-1-[4-pyridinyl]-2-propen-1-one) could have beneficial effects on plaque formation and composition. Approach and Results: ApoE −/ − (apolipoprotein E deficient) mice treated with 3PO (50 µg/g, ip; 4×/wk, 4 weeks) showed a metabolic switch toward ketone body formation. Treatment of ApoE −/− Fbn1 C1039G+/− mice with 3PO (50 µg/g, ip) either after 4 (preventive, twice/wk, 10 weeks) or 16 weeks of Western diet (curative, 4×/wk, 4 weeks) inhibited intraplaque neovascularization by 50% and 38%, respectively. Plaque formation was significantly reduced in all 3PO-treated animals. This effect was independent of intraplaque neovascularization. In vitro experiments showed that 3PO favors an anti-inflammatory M2 macrophage subtype and suppresses an M1 proinflammatory phenotype. Moreover, 3PO induced autophagy, which in turn impaired NF-κB (nuclear factor-kappa B) signaling and inhibited TNF-α (tumor necrosis factor-alpha)–mediated VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) upregulation. Consistently, a preventive 3PO regimen reduced endothelial VCAM-1 expression in vivo. Furthermore, 3PO improved cardiac function in ApoE −/− Fbn1 C1039G+/− mice after 10 weeks of treatment. Conclusions: Partial inhibition of glycolysis restrained intraplaque angiogenesis without affecting plaque composition. However, less plaques were formed, which was accompanied by downregulation of endothelial adhesion molecules—an event that depends on autophagy induction. Inhibition of coronary plaque formation by 3PO resulted in an overall improved cardiac function.

Carotid atherosclerosis represents a primary cause for cerebrovascular ischemic events and its contemporary management includes surgical revascularization for moderate to severe symptomatic stenoses. However, the role of invasive therapy seems to be questioned lately for asymptomatic cases. Numerous reports have suggested that the presence of neovessels within the atherosclerotic plaque remains a significant vulnerability factor and over the last decade imaging modalities have been used to identify intraplaque neovascularization in an attempt to risk-stratify patients and offer management guidance. Contrast-enhanced ultrasonography of the carotid artery is a relatively novel diagnostic tool that exploits resonated ultrasound waves from circulating microbubbles. This property permits vascular visualization by producing superior angiography-like images, and allows the identification of vasa vasorum and intraplaque microvessels. Moreover, plaque neovascularization has been associated with plaque vulnerability and ischemic symptoms lately as well. At the same time, attempts have been made to quantify contrast-enhanced ultrasonography signal using sophisticated software packages and algorithms, and to correlate it with intraplaque microvascular density. The aim of this review was to collect all recent data on the characteristics, performance, and prognostic role of contrast-enhanced ultrasonography regarding carotid stenosis management, and to produce useful conclusions for clinical practice.

OBJECTIVEThe relationship between intraplaque hypoxia and intraplaque hemorrhage (IPH) has been reported, but the details remain obscure. In this study, the authors aimed to clarify the relationship among intraplaque hypoxia, endothelial progenitor cells (EPCs), and neovascularization, which causes IPH. The histological findings of specimens obtained from carotid endarterectomy were assessed.METHODSThis study included 49 patients who underwent carotid endarterectomy. Magnetic resonance plaque imaging was performed to analyze the components of the carotid plaques, and surgical specimens were subjected to immunohistochemical analysis. The numbers of hypoxia-inducible factor-1 alpha (HIF-1α)–, CD34-, CD133-, and vascular endothelial growth factor receptor-2 (VEGFR-2)–positive cells in the carotid plaques were precisely quantified, as were the number and maximum diameter of CD31-positive microvessels.RESULTSPlaque components were judged as fibrous in 7 samples, lipid-rich in 22, and IPH in 20. The number of CD34-, VEGFR-2–, and CD133-positive cells as an EPC-specific marker was significantly correlated with the number of HIF-1α–positive cells (r = 0.9, r = 0.82, and r = 0.81, respectively). These numbers varied among the 3 plaque components (IPH > lipid-rich > fibrous). The number and maximum luminal diameter of CD31-positive microvessels were also significantly correlated with the number of HIF-1α–positive cells (r = 0.85 and r = 0.89, respectively) and varied among the 3 plaque components (IPH > lipid-rich > fibrous).CONCLUSIONSThe present findings suggest that intraplaque hypoxia may accelerate abnormal microvessel formation derived from EPCs, which in turn promotes IPH. The results also suggest that microvessel enlargement is a pivotal characteristic of IPH and these enlarged microvessels are immature endothelial tubes with disorganized branching and are fragile and prone to rupture.

Les maladies cardiovasculaires, principalement causées par l'athérosclérose, demeurent la première cause de mortalité dans le monde. L'athérosclérose est une maladie inflammatoire chronique de la paroi vasculaire provoquée par l'internalisation de lipides dans l'espace sous-endothéliale. Cette accumulation anormale déclenche l'infiltration de leucocytes et l'activation des cellules musculaires lisses (CML). Plus que l'obstruction des vaisseaux, l'instabilité et la rupture des plaques sont considérées comme les événements les plus délétères à l'origine d'infarctus du myocarde par exemple. Les deux principaux processus responsables de l'instabilité des plaques sont la calcification vasculaire et la néovascularisation intraplaque. La calcification vasculaire consiste en une minéralisation de la plaque d'athérosclérose sous forme de micro-calcifications et de macro-calcifications. Si cette dernière a été considérée comme stabilisatrice, elle diminue aussi l'élasticité des vaisseaux contribuant à l'hypertension, à la sténose aortique et à la vulnérabilité des plaques. Quant à la néovascularisation intraplaque, elle résulte de la formation de zones hypoxiques intraplaques qui provoque la formation de néovaisseaux immatures et perméables. L'angiogenèse intraplaque favorise la progression des plaques et accroît le risque de rupture. Nous cherchons à identifier ici les mécanismes responsables de ces deux phénomènes. La compréhension des mécanismes sous-jacents pourrait en effet ouvrir la voie à de nouvelles cibles thérapeutiques.Grâce à une approche multi-omics, nous avons identifié le récepteur nucléaire Rev-erbα comme un facteur clé particulièrement dérégulé dans les cellules de patients diabétiques ayant un haut risque cardiovasculaire comparé aux cellules de patients diabétiques avec un bas risque cardiovasculaire. Rev-erbα est un inhibiteur de la transcription, activé par des ligands naturels ou synthétiques, impliqué dans la régulation du métabolisme lipidique et de la réponse inflammatoire. Par ailleurs, des expériences de microdissection laser réalisées sur des endartériectomies humaines montrent que l'expression de REV-ERBα est plus faible dans les zones calcifiées et vascularisées suggérant un rôle protecteur de REV-ERBα.Dans un modèle de souris LDLr-/- âgées de 18 mois, la délétion de Rev-erbα accélère la progression et la complexité de la plaque. Par ailleurs, une analyse transcriptomique menée sur les aortes de ces souris révèle que les gènes associés aux voies de la calcification vasculaire et de l'angiogenèse intraplaque sont particulièrement enrichis lorsque Rev-erbα est délété suggérant que Rev-erbα protégerait contre l'athérosclérose, la calcification vasculaire et la néovascularisation.La déficience en Rev-erbα favorise en effet le développement de l'athérosclérose, augmente le dépôt de calcium et induit la différenciation ostéoblastique des CML. Cet effet sur la différenciation ostéoblastique des CML est amplifié en présence de cytokines pro-inflammatoires in vitro. Des analyses transcriptomiques réalisées sur CML en cours de différentiation nous ont permis d'identifier la hyaluronidase Cemip comme facteur important dans le rôle que joue Rev-erbα sur la différenciation ostéoblastique.Par ailleurs, l'analyse d'artères brachiocéphaliques par 3DISCO montre que l'absence de Rev-erbα favorise le développement d'un réseau vasculaire intraplaque plus complexe et immature que chez les souris contrôles. Au niveau moléculaire, il semblerait que Rev-erbα contrôle l'expression et de la sécrétion de facteurs pro-angiogéniques de façon cellule-spécifique.En conclusion, Rev-erbα apparaît comme un régulateur clé de la calcification vasculaire et de la sécrétion des facteurs pro-angiogéniques par les cellules de la plaque. Ces résultats permettent d'identifier Rev-erbα comme une nouvelle cible thérapeutique prometteuse pour réduire le risque cardiovasculaire résiduel chez les patients à très haut risque cardiovasculaire
Cardiovascular disease, mainly caused by atherosclerosis, remains the leading cause of death worldwide. Atherosclerosis is a chronic inflammatory disease of the vascular wall caused by the internalization of lipids into the subendothelial space. This abnormal accumulation triggers leukocyte infiltration and smooth muscle cell (SMC) activation. More than vascular occlusion, plaque instability and rupture are considered to be the most deleterious events at the origin of myocardial infarction, for exemple. The two main processes responsible for plaque instability are vascular calcification and intraplaque neovascularization. Vascular calcification is the mineralization of atherosclerotic plaque in the form of micro-calcifications and macro-calcifications. While the latter is considered stabilizing, it also reduces vascular elasticity and contributes to hypertension, aortic stenosis, and plaque vulnerability. Intraplaque neovascularization results from the formation of intraplaque hypoxic zones, leading to the formation of immature, permeable neovessels. Intraplaque angiogenesis promotes plaque progression and increases the risk of rupture. Our aim is to identify the mechanisms responsible for these two phenomena. Understanding the underlying mechanisms may provide new therapeutic targets.Using a multi-omics approach, we identified the nuclear receptor Rev-erbα as a key factor deregulated in cells from diabetic patients at high cardiovascular risk compared to cells from diabetic patients at low cardiovascular risk. Rev-erbα is a natural or synthetic ligand-activated transcription inhibitor involved in the regulation of lipid metabolism and inflammatory response. Furthermore, laser microdissection experiments performed on human endarterectomies show that REV-ERBα expression is lower in calcified and vascularized areas, suggesting a protective role for REV-ERBα.In an 18-month-old LDLr-/- mouse model, deletion of Rev-erbα accelerates plaque progression and complexity. Furthermore, transcriptomic analysis of aortas from these mice revealed that genes associated with vascular calcification and intraplaque angiogenesis pathways are enriched when Rev-erbα is deleted, suggesting that Rev-erbα protects against atherosclerosis, vascular calcification and neovascularization. Rev-erbα deficiency promotes the development of atherosclerosis, increases calcium deposition and induces osteoblastic differentiation of SMC. This effect on osteoblastic differentiation of SMC is enhanced in the presence of pro-inflammatory cytokines in vitro. Transcriptomic analyses performed on differentiating SMC allowed us to identify the hyaluronidase Cemip as an important factor in the role of Rev-erbα in osteoblastic differentiation. Furthermore, 3DISCO analysis of brachiocephalic arteries shows that the absence of Rev-erbα promotes the development of a more complex and immature intraplaque vascular network than in control mice. At the molecular level, Rev-erbα appears to control the expression and secretion of pro-angiogenic factors in a cell-specific manner.In conclusion, Rev-erbα appears to be a key regulator of vascular calcification and secretion of pro-angiogenic factors by plaque cells. These results identify Rev-erbα as a promising new therapeutic target for reducing residual cardiovascular risk in patients at very high cardiovascular risk

Malgré des décennies d'administration de traitements hypocholestérolémiants, de stratégies de prévention et d'efforts de recherche, les maladies cardiovasculaires, principalement causées par l'athérosclérose, restent la principale cause de décès dans le monde. De nouvelles thérapies sont donc indispensables pour réduire le risque cardiovasculaire résiduel et prévenir les événements athéro-thrombotiques. Plus que la sténose de la lumière artérielle, il est désormais admis que l’instabilité et la rupture de la plaque d'athérome sont les événements les plus délétères au cours de l’athérogenèse. Parmi les processus déclenchant l'instabilité de la plaque, il a été montré que la néovascularisation intraplaque accélère la croissance de la lésion, induit sa rupture et atténue les bénéfices des traitements hypocholestérolémiants comme les statines chez l'Homme. Il est intéressant de noter que l'administration locale de modulateurs de l'angiogenèse réduit non seulement la taille des lésions mais aussi la survenue d’événements cardiovasculaires aigus chez l'Homme, ce qui souligne la pertinence de ces approches thérapeutiques dans le contexte de la prévention de l’instabilité de la plaque. Cependant, les inhibiteurs actuels de l'angiogenèse sont utilisés de manière systémique et entraînent des événements cardiovasculaires secondaires indésirables, ce qui plaide en faveur de l'identification de nouvelles cibles pharmacologiques.Utilisant une approche transcriptomique sur les cellules circulantes issues de patients diabétiques à haut et faible risque cardiovasculaire, avec des expériences de microdissection sur endartériectomies humaines, nous avons déterminé que la faible expression de REV-ERBα est associée à des plaques d'athérosclérose avancées et vascularisées chez l’Homme. Dans le fond pro-athérogénique LDLr-/-, la déficience en Rev-erbα accélère la progression et la complexification de la plaque chez les souris âgées de 18 mois, nourries en régime standard. En utilisant une technique d’imagerie de l'organe entier sur l’artère brachiocéphalique, nous avons observé que ces souris LDLr-/-Rev-erbα-/- présentent un réseau de vaisseaux intraplaques plus développé, complexe et immature que les souris LDLr-/-Rev-erbα+/+. De manière intéressante, à ce réseau vasculaire intraplaque semblent aussi associés des noyaux vasculogéniques. En outre, la délétion de Rev-erbα dans notre modèle pro-athérogène est également corrélée à une induction du programme pro-angiogénique ainsi qu’à l’expression de gènes impliqués dans la sélection du phénotype endothélial « tip/stalk-cell » et de gènes associés aux capacités migratoires, prolifératives et de détection de l’hypoxie des cellules progénitrices endothéliales ; Ces cellules étant respectivement impliquées dans la formation et la croissance des vaisseaux ainsi que dans les processus vasculogéniques. En effet, la déficience de Rev-erbα augmente non seulement, ex vivo le bourgeonnement vasculaire à partir d’anneaux aortiques stimulés par VEGF mais aussi in vivo le développement du plexus vasculaire rétinien du nouveau-né. En conclusion, nous avons identifié le récepteur nucléaire Rev-erb-α comme un inhibiteur de la néovascularisation intraplaque chez la souris et l'Homme, et par conséquent REV-ERB-α semble représenter une cible pharmacologique putative pour stabiliser la plaque, en particulier chez les patients à haut risque cardiovasculaire
Despite decades of lipid-lowering treatments, prevention strategies, and research efforts, cardiovascular diseases, mainly caused by atherosclerosis, remain the leading cause of death worldwide. New therapies are therefore essential to lower the residual cardiovascular risk and prevent atherothrombotic events. More than stenosis of the arterial lumen, it is now accepted that atherosclerotic plaque instability and rupture are the most deleterious events during atherogenesis. Among the processes triggering plaque instability, intraplaque neovascularization has been shown to accelerate lesion growth, induce rupture, and attenuate the benefits of lipid-lowering treatments such as statins in humans. Interestingly, local administration of angiogenesis modulators, via anti-VEGF eluting stents, reduces not only lesion size and the presence of intraplaque neovascularization, but also the occurrence of acute cardiovascular events in humans. This emphasizes the relevance of such therapeutic approaches in preventing plaque instability. However, current angiogenesis inhibitors are used systemically and are associated with major cardiovascular events, arguing for the identification of new pharmacological targets. Using a transcriptomic approach on circulating cells from high- and low-cardiovascular-risk diabetic patients, with microdissection experiments on human endarterectomies, we determined that a low expression of the nuclear receptor and transcription inhibitor REV-ERBα is associated with advanced and vascularized atherosclerotic plaques in humans. This suggests a role for REV-ERB-α not only in preventing plaque instability but also intraplaque neovascularization.Indeed, in 18-month-old LDLr-/- mice fed a chow diet, Rev-erbα deficiency accelerates plaque progression and complexification. Using a whole organ imaging technique on the brachiocephalic artery, we observed that these LDLr-/-Rev-erbα-/- mice exhibit a more developed, complex, and immature intraplaque vessel network than LDLr-/-Rev-erbα+/+ mice. Interestingly, this intraplaque vascular network is also associated with the presence of vasculogenic nuclei. At the molecular level, the Rev-erbα deficiency in our pro-atherogenic model is also correlated with an induction of the pro-angiogenic program, as well as with the expression of genes involved in the selection of the endothelial “tip/stalk-cell” phenotypes and genes associated with the migratory, proliferative and hypoxia-sensing capacities of the endothelial progenitor cells; these cells being respectively involved in vessel formation and growth, and in vasculogenic processes. Indeed, Rev-erbα deficiency not only increases the ex vivo vascular sprouting from VEGF-stimulated aortic rings but also accelerates the in vivo retinal vascular plexus development. In conclusion, we have identified the nuclear receptor Rev-erb-α as an inhibitor of angiogenesis and intraplaque neovascularization in mice and humans. Therefore, REV-ERB-α represents a putative pharmacological target for stabilizing the atherosclerotic plaque to prevent acute cardiovascular events, particularly in high-risk patients

Coronary artery disease remains the major cause of morbidity and mortality on a global scale. Intimal thickening and fatty streaks represent early adaptive vascular changes, which are often regressive. Pathological intimal thickening represents the earliest progressive atherosclerotic lesion characterized by a focal accumulation of smooth muscle cells and acellular areas, often associated with lipid pools. Fibroatheroma is characterized by a necrotic core and can be split into early and late fibroatheroma, where macrophage apoptosis and defective efferocytosis play important roles in lesion progression. Intraplaque hypoxia is believed to result in neovascularization with subsequent intraplaque haemorrhage because of immature and leaky microvessels. Due to excessive cholesterol in remnants of erythrocyte membranes, intraplaque haemorrhage may result in rapid progression of necrotic core and plaque destabilization. Healed plaque rupture has been well delineated as an important mechanism of gradual luminal narrowing, where changes in collagen deposition allow recognition of rupture and healing sites. Calcification results from apoptosis of smooth muscle cells and macrophages or may also be caused by active release of cellular vesicles involved in calcium haemostasis. Extracellular matrix changes are associated with progression of atherosclerosis, while integrin signalling has been recognized as an important outside-in transcellular target of the inflammatory response.

Coronary artery disease remains the major cause of morbidity and mortality on a global scale. Intimal thickening and fatty streaks represent early adaptive vascular changes, which are often regressive. Pathological intimal thickening represents the earliest progressive atherosclerotic lesion characterized by a focal accumulation of smooth muscle cells and acellular areas, often associated with lipid pools. Fibroatheroma is characterized by a necrotic core and can be split into early and late fibroatheroma, where macrophage apoptosis and defective efferocytosis play important roles in lesion progression. Intraplaque hypoxia is believed to result in neovascularization with subsequent intraplaque haemorrhage because of immature and leaky microvessels. Due to excessive cholesterol in remnants of erythrocyte membranes, intraplaque haemorrhage may result in rapid progression of necrotic core and plaque destabilization. Healed plaque rupture has been well delineated as an important mechanism of gradual luminal narrowing, where changes in collagen deposition allow recognition of rupture and healing sites. Calcification results from apoptosis of smooth muscle cells and macrophages or may also be caused by active release of cellular vesicles involved in calcium haemostasis. Extracellular matrix changes are associated with progression of atherosclerosis, while integrin signalling has been recognized as an important outside-in transcellular target of the inflammatory response.