Angiogenesis

APJ has been extensively described in the pathophysiology of angiogenesis and cell proliferation. The prognostic value of APJ overexpression in many diseases is now established. This study aimed to design a PET radiotracer that specifically binds to APJ. Apelin-F13A-NODAGA (AP747) was synthesized and radiolabeled with gallium-68 ([Ga]Ga-AP747). Radiolabeling purity was excellent (> 95%) and stable up to 2 h. Affinity constant of [Ga]Ga-AP747 was measured on APJ-overexpressing colon adenocarcinoma cells and was in nanomolar range. Specificity of [Ga]Ga-AP747 for APJ was evaluated in vitro by autoradiography and in vivo by small animal PET/CT in both colon adenocarcinoma mouse model and Matrigel plug mouse model. Dynamic of [Ga]Ga-AP747 PET/CT biodistributions was realized on healthy mice and pigs for two hours, and quantification of signal in organs showed a suitable pharmacokinetic profile for PET imaging, largely excreted by urinary route. Matrigel mice and hindlimb ischemic mice were submitted to a 21-day longitudinal follow-up with [Ga]Ga-AP747 and [Ga]Ga-RGD small animal PET/CT. [Ga]Ga-AP747 PET signal in Matrigel was significantly more intense than that of [Ga]Ga-RGD. Revascularization of the ischemic hind limb was followed by LASER Doppler. In the hindlimb, [Ga]Ga-AP747 PET signal was more than twice higher than that of [Ga]Ga-RGD on day 7, and significantly superior over the 21-day follow-up. A significant, positive correlation was found between the [Ga]Ga-AP747 PET signal on day 7 and late hindlimb perfusion on day 21. We developed a new PET radiotracer that specifically binds to APJ, [Ga]Ga-AP747 that showed more efficient imaging properties than the most clinically advanced tracer of angiogenesis, [Ga]Ga-RGD.France Life Imagin

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Extracellular Vesicles in Angiogenesis

ReviewA ngiogenesis, defined as the formation of new blood vessels from a pre-existing vascular network, naturally occurs in an organism during growth and development and also in response to injury to restore a tissue's blood supply and promote wound healing. The new vessels can be formed by either sprouting angiogenesis, where endothelial cells (ECs) form sprouts that grow toward an angiogenic stimulus, or intussus-ceptive angiogenesis, where interstitial tissues invade the existing vessels and form transvascular tissue pillars that expand and split the vessel. 1 Sprouting angiogenesis comprises several steps: enzymatic degradation of the vessel's basement membrane , EC proliferation, migration, sprouting, branching, and tube formation. The stabilization and maturation of the newly formed vascular structures require the recruitment of pericytes, the deposition of extracellular matrix, and mechanical stimulation by the shear stress. In healthy tissues, angiogenesis is tightly regulated by a precise balance between stimulatory and inhibitory signals. 2 Abnormal blood vessel growth occurs when this balance is disturbed and is a major cause of numerous diseases, such as cancer, atherosclerosis, corneal neovas-cularization, rheumatoid arthritis, or ischemic diseases. During the past decade, the vesicles released by different cell types have been shown to be important mediators during the process of blood vessel formation and, as such, they have attracted particular interest among researchers from various fields of biology and medicine, including angiogenesis. 3,4 Longtime considered as inert debris or a hallmark of cell injury, extracellular vesicles (EVs), which include apoptotic bodies, microvesicles, and exosomes, have emerged as an important tool for intercellular communications in normal physiology and in pathophysiological conditions. 5,6 Indeed, EVs function as the carriers of small bioactive molecules, such as Review Circulation Research is available at http://circres.ahajournals.org Abstract: During the past decade, extracellular vesicles (EVs), which include apoptotic bodies, microvesicles, and exosomes, have emerged as important players in cell-to-cell communication in normal physiology and pathological conditions. EVs encapsulate and convey various bioactive molecules that are further transmitted to neighboring or more distant cells, where they induce various signaling cascades. The message delivered to the target cells is dependent on EV composition, which, in turn, is determined by the cell of origin and the surrounding microenvironment during EV biogenesis. Among their multifaceted role in the modulation of biological responses, the involvement of EVs in vascular development, growth, and maturation has been widely documented and their potential therapeutic application in regenerative medicine or angiogenesis-related diseases is drawing increasing interest. EVs derived from various cell types have the potential to deliver complex information to endothelial cells and to induce either pro-or antiangiogenic signaling. As dynamic systems, in response to changes in the microenvironment, EVs adapt their cargo composition to fine-tune the process of blood vessel formation. This article reviews the current knowledge on the role of microvesicles and exosomes from various cellular origins in angiogenesis, with a particular emphasis on the underlying mechanisms, and discusses the main challenges and prerequisites for their therapeutic applications. (Circ Res

Microvesicles and Cancer Associated Thrombosis

Microvesicles (MVs) are small membrane enclosed structures released into the extracellular space by virtually all cell types. Their composition varies according to the cell origin and the stimulus which caused their formation. They harbor functional molecules and participate in intercellular communication. Endothelium, inflammatory cells, and cancer cells produce procoagulant MVs which contribute to cancer-associated thrombosis (CAT) in animal models. The tissue factor (TF) conveyed by these MVs was shown to play a key role in different animal models of experimental CAT. Alternatively, other molecular mechanisms involving polyphosphates or phosphatidylethanolamine could also be involved. In clinical practice, an association between an increase in the number of TF-positive or the procoagulant activity of these MVs and the occurrence of CAT has indeed been demonstrated in pancreatic-biliary cancers, suggesting that they could behave as a biomarker predictive for CAT. However, to date, this association was not confirmed in other types of cancer. Potential causes explaining this limited associated between MVs and CAT are (1) the diversity of mechanisms associating MVs and different types of cancer; (2) a more complex role of MVs in hemostasis integrating their anticoagulant and fibrinolytic activity; and (3) the lack of sensitivity, reproducibility, and standardization of current methodologies permitting measurement of MVs. Each of these hypotheses constitutes an interesting exploration path for a future reassessment of the clinical interest of the MVs in CAT

TRAIL/Apo2L mediates the release of procoagulant endothelial microparticles induced by thrombin in vitro: a potential mechanism linking inflammation and coagulation.

peer reviewedMicroparticles are small vesicles playing a crucial role in cell communication by promoting prothrombotic and proinflammatory responses. However, the molecular mechanisms underlying their release are still elusive. We previously established that thrombin promoted the generation of endothelial microparticles (EMPs). In the present study, gene profiling identified TRAIL/Apo2L, a cytokine belonging to the tumor necrosis factor-alpha superfamily, as a target of thrombin. Thrombin increased the expression of cell-associated and soluble forms of TRAIL (sTRAIL) in HMEC-1 cells and human umbilical vein endothelial cells (HUVECs). Blocking TRAIL by specific antibodies or by small interfering RNA reduced both the number and the procoagulant activity of EMPs released by thrombin. Consistent with an involvement of sTRAIL in thrombin-induced EMP release, we showed that (1) exogenously added sTRAIL generated procoagulant EMPs; (2) supernatants from thrombin-stimulated endothelial cells induced EMP release by HMEC-1 cells and HUVECs, whereas those recovered from TRAIL knockdown endothelial cells displayed no effect. TRAIL/TRAIL-R2 complex mediated EMP release by initiating the recruitment of adaptor proteins and the activation of nuclear factor kappaB. Moreover, sTRAIL modulated intercellular adhesion molecule-1 and interleukin-8 expression induced by thrombin by a downstream pathway involving nuclear factor kappaB activation. Our data reveal a novel mechanism controlling EMP release and identify TRAIL as a key partner in the pathway linking coagulation and inflammation elicited by thrombin

Developmental programming of arterial hypertension in a rat model of intrauterine growth restriction: impaired functionality of endothelial progenitor cells associated to oxidative stress and cellular

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Paracrine Effects of Adipose-Derived Cellular Therapies in an in Vitro Fibrogenesis Model of Human Vocal Fold Scarring

International audienceObjectives/Hypothesis. Vocal folds (VF) scarring leads to severe dysphonia which negatively impacts daily life of patients. Current therapeutic options are limited due in large part to the high complexity of the micro-structure of the VF. Innovative therapies derived from adipose tissue such as stromal vascular fraction (SVF) or adipose derived stromal/ stem cells (ASC) are currently being evaluated in this indication and paracrine anti-fibrotic effects are considered as predominant mechanisms. Methods. The paracrine anti-fibrotic effects of SVF and ASC from healthy donors were tested in an innovative in vitro fibrogenesis model employing human VF fiboblasts (hVFF) and the principles of macromolecular crowding (MMC). Biosynthesis of collogen and alpha-smooth-muscle actin (aSMA) expression in hVFF were quantified after five days of indirect coculture with ASC or SVF using silver stain, western blot and RT-qPCR analysis. Results. Fibrogenesis was promoted by addition of transforming growth factor beta 1 (TGFb1) combined with MMC characterized by an enhanced deposition of fibrillar collagens and the acquisition of a myofibroblast phenotype (overexpression of aSMA). Adipose-derived therapies led to a reduction in the aSMA expression and the collagen content was lower in hVFF co-cultivated with SVF. Conclusions. ASC and SVF promoted significant prevention of fibrosis in an in vitro fibrogenesis model through paracrine mechanisms, supporting further development of adipose-derived cellular therapies in VF scarring

SIRT1 Deficiency in endothelial progenitor cells drives pro-senescent microparticles release through MKK6 upregulation

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Distinctive endothelial and inflammatory profiles characterize kidney transplants from extended criteria donors

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SIRT1 Deficiency in endothelial progenitor cells drives pro-senescent microparticles release through MKK6 upregulation

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