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Search for other papers by Majid Almansouri in
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Search for other papers by Pooja Patel in
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Healthy Lifespan Institute HELSI, University of Sheffield, Medical School, Sheffield, UK
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Atherosclerosis is characterised by abnormal lipid and cell accumulation within arterial layers that leads to disturbed blood flow. Modified cholesterol forms such as oxidised low-density lipoprotein (oxLDL) enter cells altering their phenotype, triggering over-exuberant repair and arterial occlusion, myocardial infarction or stroke. We hypothesised that oxLDL enters vascular wall cells and induces interleukin-1β (IL-1β) secretion, potentially via a caspase-1/NLRP3 mechanism. Human coronary artery endothelial cells (HCAEC) and smooth muscle cells (HCASMC), isolated from different donors, were cultured and stimulated (primed) with pro-inflammatory cytokines TNFα and IL-1α (10 ng/mL each, for 48 h), followed by incubation with human oxLDL (10–50 ug/mL) for up to 6 h. Inhibitors of caspase-1 (YVAD), NLRP3 (MCC950) and gasdermin D (disulfiram) were added 1 h before oxLDL. Cell lysates and culture supernatants were collected and analysed for IL-1β using ELISA. Microscopy imaging showed oxLDL entered stimulated cells and formed particles. OxLDL at 20 and 50 ug/mL induced the maximum release of IL-1β from stimulated HCASMCs and HCAECs, respectively, compared to control. Inhibition of either NLRP3, caspase-1 or gasdermin D significantly reduced the release of IL-1β (4-fold, P < 0.0001; 14-fold, P < 0.0001, 1.5-fold, P < 0.0003, respectively) in HCAEC. In contrast, in HCASMCs, only caspase-1 inhibition reduced the release of IL-1β (2.1-fold, P < 0.0001). HCAECs and HCASMCs elicited the release of IL-1β in response to the same stimulus via different mechanisms. In HCAECs, released IL-1β potentially exits via a GSDMD-induced membrane pore. These data suggest that caspase-1 or gasdermin D inhibition is likely to be effective vessel wall cell-specific strategies for the reduction of atherosclerosis.
Search for other papers by Paul H A Quax in
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Search for other papers by Marie-José T H Goumans in
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Search for other papers by Vladimir Y Bogdanov in
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Search for other papers by Vladimir N Khirmanov in
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As we enter year 3 of SARS-CoV-2 pandemic, long-term consequences of COVID-19 have become a major public health issue worldwide; however, the molecular and cellular underpinnings of ‘long COVID’ remain very poorly understood. A paradigm has recently emerged that thrombo-inflammatory consequences of SARS-CoV-2’s impact on endothelial cells and platelets likely play a significant role in the development of chronic symptomatology associated with COVID-19. In this brief overview, we discuss the recent findings pertaining to the detection of SARS-CoV-2 virions in vascular cell subtypes, the contribution of the coagulation system to the development of ‘long COVID’, and the potential role of stem/progenitor cells in the viral and thrombotic dissemination in this disorder.
Search for other papers by Jordan C Langston in
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Search for other papers by Michael T Rossi in
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Search for other papers by Qingliang Yang in
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Search for other papers by Laurie E Kilpatrick in
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Search for other papers by Balabhaskar Prabhakarpandian in
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Department of Mechanical Engineering, Temple University, Philadelphia, Pennsylvania, USA
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During sepsis, defined as life-threatening organ dysfunction due to dysregulated host response to infection, systemic inflammation activates endothelial cells and initiates a multifaceted cascade of pro-inflammatory signaling events, resulting in increased permeability and excessive recruitment of leukocytes. Vascular endothelial cells share many common properties but have organ-specific phenotypes with unique structure and function. Thus, therapies directed against endothelial cell phenotypes are needed to address organ-specific endothelial cell dysfunction. Omics allow for the study of expressed genes, proteins and/or metabolites in biological systems and provide insight on temporal and spatial evolution of signals during normal and diseased conditions. Proteomics quantifies protein expression, identifies protein–protein interactions and can reveal mechanistic changes in endothelial cells that would not be possible to study via reductionist methods alone. In this review, we provide an overview of how sepsis pathophysiology impacts omics with a focus on proteomic analysis of mouse endothelial cells during sepsis/inflammation and its relationship with the more clinically relevant omics of human endothelial cells. We discuss how omics has been used to define septic endotype signatures in different populations with a focus on proteomic analysis in organ-specific microvascular endothelial cells during sepsis or septic-like inflammation. We believe that studies defining septic endotypes based on proteomic expression in endothelial cell phenotypes are urgently needed to complement omic profiling of whole blood and better define sepsis subphenotypes. Lastly, we provide a discussion of how in silico modeling can be used to leverage the large volume of omics data to map response pathways in sepsis.
Center for Engineering MechanoBiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Center for Engineering MechanoBiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Hutchinson–Guilford Progeria syndrome (HGPS) is a rare genetic disease of premature aging and early death due to cardiovascular disease. The arteries of HGPS children and mice are pathologically stiff, and HGPS mice also display reduced arterial contractility. We recently showed that reduced contractility is an early event in HGPS and linked to an aberrantly low expression of smooth muscle myosin heavy chain (smMHC). Here, we have explored the basis for reduced smMHC abundance and asked whether it is a direct effect of progerin expression or a longer-term adaptive response. Myh11, the gene encoding for smMHC, is regulated by myocardin-related transcription factors (MRTFs), and we show that HGPS aortas have a reduced MRTF signature. Additionally, smooth muscle cells (SMCs) isolated from HGPS mice display reduced MRTF nuclear localization. Acute progerin expression in WT SMCs phenocopied both the decrease in MRTF nuclear localization and expression of Myh11 seen in HGPS. Interestingly, RNA-mediated depletion of MRTF-A in WT SMCs reproduced the preferential inhibitory effect of progerin on Myh11 mRNA relative to Acta2 mRNA. Our results show that progerin expression acutely disrupts MRTF localization to the nucleus and suggest that the consequent decrease in nuclear coactivator activity can help to explain the reduction in smMHC abundance and SMC contractility seen in HGPS.
Search for other papers by Alba Lopez Rioja in
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Search for other papers by Harry Mellor in
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The endothelial barrier is a tightly regulated gateway in the transport of material between circulation and the tissues. Inflammatory mediators such as thrombin are able to open paracellular spaces in the endothelial monolayer to allow the extravasation of plasma proteins and leukocytes. Here we show that the protein SLIT-ROBO Rho GTPase-activating protein 2 (srGAP2) plays a critical role in regulating the extent of thrombin-mediated opening. We show that srGAP2 is not required for normal barrier function in resting endothelial cells, but that depletion of srGAP2 significantly increases the magnitude and duration of junctional opening in response to thrombin. We show that srGAP2 acts to switch off RhoA signaling after the contraction phase of thrombin-induced permeability, allowing respreading of cells and reformation of the barrier. srGAP2 is also required for effective restoration of the barrier after treatment with two other vasoactive agents that active RhoA – TNFα and angiotensin II. Taken together, we show that srGAP2 has a general function in controlling RhoA signaling in endothelial permeability, acting to limit the degree and duration of opening, by triggering the switch from endothelial cell contraction to respreading.
Molecular Mechanisms and Experimental Therapy in Oncology Program (Oncobell), Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
Departament de Ciències Fisiològiques, Facultat de Medicina i Ciències de la Salut (Campus de Bellvitge), Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain
Search for other papers by Ferran Medina-Jover in
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Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
Faculty of Medicine and Health Sciences, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain
Search for other papers by Antoni Riera-Mestre in
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Molecular Mechanisms and Experimental Therapy in Oncology Program (Oncobell), Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
Departament de Ciències Fisiològiques, Facultat de Medicina i Ciències de la Salut (Campus de Bellvitge), Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain
Search for other papers by Francesc Viñals in
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Angiogenesis is an essential process for correct development and physiology. This mechanism is tightly regulated by many signals that activate several pathways, which are constantly interacting with each other. There is mounting evidence that BMP9/ALK1 pathway is essential for a correct vessel maturation. Alterations in this pathway lead to the development of hereditary haemorrhagic telangiectasias. However, little was known about the BMP9 signalling cascade until the last years. Recent reports have shown that while BMP9 arrests cell cycle, it promotes the activation of anabolic pathways to enhance endothelial maturation. In light of this evidence, a new criterion for the classification of cytokines is proposed here, based on the physiological objective of the activation of anabolic routes. Whether this activation by a growth factor is needed to sustain mitosis or to promote a specific function such as matrix formation is a critical characteristic that needs to be considered to classify growth factors. Hence, the state-of-the-art of BMP9/ALK1 signalling is reviewed here, as well as its implications in normal and pathogenic angiogenesis.
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Search for other papers by Cristina Maria Failla in
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Interleukins (ILs) are the group of cytokines firstly identified as expressed by leukocytes and playing different immunomodulatory functions. With increasing evidence of a constant crosstalk between leukocytes and endothelial cells in the regulation of immune cell differentiation and activation, a role of ILs also in endothelial cell stimulation and vascular inflammation has been shown. ILs act on endothelial cells both in an autocrine and a paracrine manner. In fact, a cross regulation is present among ILs expressed by different cell types, leading to amplification or blocking of the initial inflammatory signal with the secretion of additional ILs or involvement of other adjacent cells and tissues. Based on selective structural features, ILs can be divided into four major groups, a fifth group comprises ILs that do not fit into any of the other four. Most of the ILs playing a role in endothelial cell activation belong to the IL1-like cytokine group, but the number of ILs involved in vascular inflammation is constantly growing, and a special contribution of IL6, IL8, and IL17 has been underlined. This review aims at presenting current knowledge and at underling missing information about the role of IL in activating endothelial cells in selected pathological settings such as tumours, psoriasis, systemic sclerosis, and viral infection.
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Search for other papers by Mark Ross in
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Breast cancer chemotherapy, although very potent against tumour tissue, results in significant cardiovascular toxicity. The focus of research in this area has been predominantly towards cardiotoxicity. There is limited evidence detailing the impact of such treatment on the vasculature despite its central importance within the cardiovascular system and resultant detrimental effects of damage and dysfunction. This review highlights the impact of chemotherapy for breast cancer on the vascular endothelium. We consider the most likely mechanisms of endothelial toxicity to be through direct damage and dysfunction of the endothelium. There are sharp consequences of these detrimental effects as they can lead to cardiovascular disease. However, there is potential for exercise to alleviate some of the vascular toxicity of chemotherapy, and the evidence for this is provided. The potential role of exercise in protecting against vascular toxicity is explained, highlighting the recent in-human and animal model exercise interventions. Lastly, the mediating mechanisms of exercise protection of endothelial health is discussed, focusing on the importance of exercise for endothelial health, function, repair, inflammation and hyperlipidaemia, angiogenesis, and vascular remodelling. These are all important counteracting measures against chemotherapy-induced toxicity and are discussed in detail.
Search for other papers by Wessel S Rodenburg in
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Leeuwenhoek Centre for Advanced Microscopy, Section Molecular Cytology at Swammerdam Institute for Life Sciences at University of Amsterdam, Amsterdam, the Netherlands
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Rho GTPases are small signalling G-proteins that are central regulators of cytoskeleton dynamics, and thereby regulate many cellular processes, including the shape, adhesion and migration of cells. As such, Rho GTPases are also essential for the invasive behaviour of cancer cells, and thus involved in several steps of the metastatic cascade, including the extravasation of cancer cells. Extravasation, the process by which cancer cells leave the circulation by transmigrating through the endothelium that lines capillary walls, is an essential step for metastasis towards distant organs. During extravasation, Rho GTPase signalling networks not only regulate the transmigration of cancer cells but also regulate the interactions between cancer and endothelial cells and are involved in the disruption of the endothelial barrier function, ultimately allowing cancer cells to extravasate into the underlying tissue and potentially form metastases. Thus, targeting Rho GTPase signalling networks in cancer may be an effective approach to inhibit extravasation and metastasis. In this review, the complex process of cancer cell extravasation will be discussed in detail. Additionally, the roles and regulation of Rho GTPase signalling networks during cancer cell extravasation will be discussed, both from a cancer cell and endothelial cell point of view.
