scholarly journals Nucleic Acid Sensing in the Tumor Vasculature

2021 ◽  
Author(s):  
Adrian M. Baris ◽  
Eugenia Fraile-Bethencourt ◽  
Sudarshan Anand
Keyword(s):  
Endothelial Cells ◽  
Nucleic Acid ◽  
Immune Responses ◽  
Tumor Vasculature ◽  
Functional Roles ◽  
Tumor Endothelium ◽  
Immunosuppressive Microenvironment ◽  
Unique Ability ◽  
Acid Sensors

Endothelial cells form a powerful interface between tissues and immune cells. In fact, one of the underappreciated roles of endothelial cells is to orchestrate immune attention to specific sites. Tumor endothelial cells have a unique ability to dampen the immune responses and thereby maintain an immunosuppressive microenvironment. Recent approaches to trigger immune responses in cancers have focused on activating nucleic acid sensors such as cGAS/STING in combination with immunotherapies. In this review, we present a case for targeting nucleic acid sensing pathways within the tumor vasculature to invigorate tumor immune responses. We introduce two specific nucleic acid sensors, the DNA sensor TREX1 and the RNA sensor RIG-I and discuss their functional roles in the vasculature. Finally, we present perspectives on how these nucleic acid sensors in the tumor endothelium can be targeted in an antiangiogenic and immune activation context. We believe understanding the role of nucleic acid sensing in the tumor vasculature can enhance our ability to design more effective therapies targeting the tumor microenvironment.

scholarly journals Nucleic Acid Sensing in the Tumor Vasculature

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4452
Author(s):  
Adrian M. Baris ◽  
Eugenia Fraile-Bethencourt ◽  
Sudarshan Anand
Keyword(s):  
Endothelial Cells ◽  
Nucleic Acid ◽  
Immune Responses ◽  
Immune Cell ◽  
Tumor Vasculature ◽  
Cell Types ◽  
Functional Roles ◽  
Tumor Endothelium ◽  
Immunosuppressive Microenvironment ◽  
Acid Sensors

Endothelial cells form a powerful interface between tissues and immune cells. In fact, one of the underappreciated roles of endothelial cells is to orchestrate immune attention to specific sites. Tumor endothelial cells have a unique ability to dampen immune responses and thereby maintain an immunosuppressive microenvironment. Recent approaches to trigger immune responses in cancers have focused on activating nucleic acid sensors, such as cGAS-STING, in combination with immunotherapies. In this review, we present a case for targeting nucleic acid-sensing pathways within the tumor vasculature to invigorate tumor-immune responses. We introduce two specific nucleic acid sensors—the DNA sensor TREX1 and the RNA sensor RIG-I—and discuss their functional roles in the vasculature. Finally, we present perspectives on how these nucleic acid sensors in the tumor endothelium can be targeted in an antiangiogenic and immune activation context. We believe understanding the role of nucleic acid-sensing in the tumor vasculature can enhance our ability to design more effective therapies targeting the tumor microenvironment by co-opting both vascular and immune cell types.

160. THE ROLE OF PHAGOCYTOSIS OF APOPTOTIC SYNCYTIAL KNOTS IN THE PREVENTION OF ENDOTHELIAL CELL ACTIVATION: AN IMPORTANT ADAPTATION FOR NORMAL PREGNANCY

2010 ◽  
Vol 22 (9) ◽  
pp. 78
Author(s):  
Q. Chen ◽  
H. Jin ◽  
P. Stone ◽  
L. Chamley
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Immune Responses ◽  
Cell Activation ◽  
Normal Pregnancy ◽  
Cytochalasin D ◽  
Endothelial Cell Activation ◽  
Endothelial Cell Surface ◽  
Large Numbers

Preeclampsia is characterised by an exaggerated inflammatory response and maternal endothelial cell activation. Syncytial knots, dead multinucleated fetal cells shed from the placenta in large numbers during all pregnancies, may be phagocytosed by maternal endothelial cells. Our previous studies showed that phagocytosis of necrotic but not apoptotic syncytial knots led to endothelial cell activation. It is known that phagocytosis of apoptotic cells leads to active tolerance of immune responses and in this study we questioned whether phagocytosis of apoptotic syncytial knots leads to suppression of the endothelial cells ability to be activated. Syncytial knots were harvested from 1st trimester placental explants. Monolayers of endothelial cells were pre-treated with apoptotic syncytial knots for 24 h. After washing, the endothelial cells were treated with the endothelial cell activators LPS, PMA, IL-6, or necrotic syncytial knots for 24 h. In some experiments the inhibitor of phagocytosis, cytochalasin D, was added into the cultures along with apoptotic syncytial knots. Endothelial cell-surface ICAM-1 was measured using cell based ELISAs. Expression of ICAM-1 by endothelial cells that had phagocytosed apoptotic syncytial knots prior to treatment with LPS, PMA, IL-6, or necrotic syncytial knots was significantly (P =/<0.003) reduced, compared to control endothelial cells that had not phagocytosed apoptotic syncytial knots. Inhibiting phagocytosis of apoptotic syncytial knots with cytochalasin D abolished this protective effect. Our data suggest phagocytosis of apoptotic syncytial knots results in the suppression of the ability of endothelial cells to be activated by a number of potent chemical activators, as well as by the physiologically relevant activator, necrotic syncytial knots. This work suggests that the release of apoptotic syncytial knots from the placenta during normal pregnancy may be a mechanism by which the fetus attempts to protect the maternal vasculature against activation.

scholarly journals Endothelial Cells in Emerging Viral Infections

2021 ◽  
Vol 8 ◽  
Author(s):  
Johanna Hol Fosse ◽  
Guttorm Haraldsen ◽  
Knut Falk ◽  
Reidunn Edelmann
Keyword(s):  
Endothelial Cells ◽  
Immune Responses ◽  
Vascular Function ◽  
Cell Function ◽  
Viral Infections ◽  
Host Immune System ◽  
Emerging Viruses ◽  
General Validity ◽  
Endothelial Cell Function

There are several reasons to consider the role of endothelial cells in COVID-19 and other emerging viral infections. First, severe cases of COVID-19 show a common breakdown of central vascular functions. Second, SARS-CoV-2 replicates in endothelial cells. Third, prior deterioration of vascular function exacerbates disease, as the most common comorbidities of COVID-19 (obesity, hypertension, and diabetes) are all associated with endothelial dysfunction. Importantly, SARS-CoV-2's ability to infect endothelium is shared by many emerging viruses, including henipaviruses, hantavirus, and highly pathogenic avian influenza virus, all specifically targeting endothelial cells. The ability to infect endothelium appears to support generalised dissemination of infection and facilitate the access to certain tissues. The disturbed vascular function observed in severe COVID-19 is also a prominent feature of many other life-threatening viral diseases, underscoring the need to understand how viruses modulate endothelial function. We here review the role of vascular endothelial cells in emerging viral infections, starting with a summary of endothelial cells as key mediators and regulators of vascular and immune responses in health and infection. Next, we discuss endotheliotropism as a possible virulence factor and detail features that regulate viruses' ability to attach to and enter endothelial cells. We move on to review how endothelial cells detect invading viruses and respond to infection, with particular focus on pathways that may influence vascular function and the host immune system. Finally, we discuss how endothelial cell function can be dysregulated in viral disease, either by viral components or as bystander victims of overshooting or detrimental inflammatory and immune responses. Many aspects of how viruses interact with the endothelium remain poorly understood. Considering the diversity of such mechanisms among different emerging viruses allows us to highlight common features that may be of general validity and point out important challenges.

Abstract 15833: LRP1 is a Novel Receptor of Bmper and Required for Pathological Angiogenesis

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Xi Li ◽  
Xinchun Pi
Keyword(s):  
Endothelial Cells ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Bmp Signaling ◽  
Functional Roles ◽  
Oxygen Induced Retinopathy ◽  
Morphogenetic Protein ◽  
Density Lipoprotein Receptor

Low density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional member of the LDL receptor family, impacting a variety of biological processes such as lipid metabolism, endocytosis and signal transduction. However, the role of LRP1 in endothelium was almost unknown. Until recently we discovered that LRP1 is a novel regulator of bone morphogenetic protein (Bmp) signaling through its association with the extracellular modulator-Bmper (Bmp-binding endothelial cell precursor-derived regulator) and regulates zebrafish vascular development. Here we studied the functional roles of LRP1 in mammalian system by performing cell culture studies with endothelial cells (ECs) and analyzing angiogenic defects in oxygen-induced retinopathy model with LRP1flox/flox;Tie2-Cre+/- mice (EC-LRP1 KO). In MECs, we observed that the activation of Src, ERK and tyrosine phosphorylation of multiple proteins were induced by Bmper and this activation was LRP1-dependent since LRP1 knockdown inhibited their activation. However, this Bmper-induced activation was not blocked by Bmp4 neutralized antibody, which suggests that LRP1 is required for Bmp4-independent signaling for Bmper. These data also indicate that Bmper and LRP1 is a novel ligand receptor pair. Moreover, we observed that LRP1 protein was induced in response to 1% hypoxia in both mouse ECs (MECs) and human retinal microvascular endothelial cells, suggesting that LRP1 is required for hypoxia induced endothelial function. In hypoxia condition, EC-LRP1 KO mice resulted in accelerated angiogenesis in retinal endothelial cells, similar to the pattern of Bmper deleted mice. Therefore, we identify that the Bmper/LRP1 signaling is a novel signaling pathway in endothelial cells and their activity regulates angiogenic responses during oxygen-induced retinopathy. This study provides mechanistic insights for angiogenesis-related pathophysiologic conditions.

scholarly journals Allogeneic Antigen Composition for Preparing Universal Cancer Vaccines

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Petr G. Lokhov ◽  
Elena E. Balashova
Keyword(s):  
Endothelial Cells ◽  
Vaccine Development ◽  
Present Report ◽  
Tumor Vasculature ◽  
Target Cells ◽  
Human Endothelial Cells ◽  
Cell Surface Antigens ◽  
Tumor Endothelium ◽  
Natural Target

Recently it was demonstrated that tumors induce specific changes to the surface of human endothelial cells thereby providing the basis for designing endothelial cell-based vaccines that directly target antigens expressed by the tumor endothelium. The present report extends these studiesin vitroby investigating the efficacy of allogeneic antigens with regard to their ability to target immune responses against the tumor vasculature since alloantigens simplify vaccine development and implementation in clinical practice. We demonstrated that allogeneic SANTAVAC (Set of All Natural Target Antigens for Vaccination Against Cancer), which presents a specifically prepared composition of cell surface antigens from tumor-stimulated endothelial cells, allows targeting of the tumor vasculature with efficacy of 17, where efficacy represents the killing rate of target cells before normal cells are adversely affected, and efficacy of 60, where efficacy represents the fold decrease in the number of target cells and directly relates to tumor growth arrest. These data suggest that allogeneic SANTAVAC may be considered an antigenic composition that following administration in the presence of respective adjuvants may be clinically tested as a therapeutic or prophylactic universal cancer vaccine without adverse side effects to the normal vasculature.

scholarly journals Role of MicroRNAs in the Pathogenesis of Coronary Artery Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Soudeh Ghafouri-Fard ◽  
Mahdi Gholipour ◽  
Mohammad Taheri
Keyword(s):  
Coronary Artery Disease ◽  
Endothelial Cells ◽  
Coronary Artery ◽  
Immune Responses ◽  
Coronary Arteries ◽  
Plaque Formation ◽  
Proliferation And Apoptosis ◽  
Regulation Of Proliferation ◽  
Artery Disease

Coronary artery disease (CAD) is the main reason of cardiovascular mortalities worldwide. This condition is resulted from atherosclerotic occlusion of coronary arteries. MicroRNAs (miRNAs) are implicated in the regulation of proliferation and apoptosis of endothelial cells, induction of immune responses and different stages of plaque formation. Up-regulation of miR-92a-3p, miR-206, miR-216a, miR-574-5p, miR-23a, miR-499, miR-451, miR-21, miR-146a, and a number of other miRNAs has been reported in CAD patients. In contrast, miR-20, miR-107, miR-330, miR-383-3p, miR-939, miR-4306, miR-181a-5p, miR-218, miR-376a-3p, and miR-3614 are among down-regulated miRNAs in CAD. Differential expression of miRNAs in CAD patients has been exploited to design diagnostic or prognostic panels for evaluation of CAD patients. We appraise the recent knowledge about the role of miRNAs in the development of diverse clinical subtypes of CAD.

scholarly journals Genomic landscapes of non-coding RNAs regulating VEGFA and VEGFC expression in endothelial cells

2021 ◽  
Author(s):  
Isidore Mushimiyimana ◽  
Vanesa Tomas Bosch ◽  
Henri Niskanen ◽  
Nicholas Downes ◽  
Pierre Moreau ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Growth Factors ◽  
Vascular Endothelial ◽  
Rna Seq ◽  
Functional Roles ◽  
Genome Wide ◽  
Non Coding Rnas ◽  
Endothelial Growth Factors ◽  
Regulatory Landscape

Vascular endothelial growth factors (VEGFs) are best known as key regulators of angiogenesis and lymphangiogenesis. Although VEGFs have been promising therapeutic targets for various cardiovascular related diseases, their regulatory landscape in endothelial cells remains elusive. Several studies have highlighted the involvement of non-coding RNAs (ncRNAs) in the modulation of VEGF expression. In this study, we investigated the role of two classes of non-coding RNAs, long ncRNA (lncRNA) and enhancer RNAs (eRNAs), in the transcriptional regulation of VEGFA and VEGFC. By integrating genome-wide global run-on (GRO-seq) and Hi-C data, we identified putative lncRNAs and eRNAs associated with VEGFA and VEGFC genes in endothelial cells. A subset of the identified putative enhancers demonstrated regulatory activity in a reporter assay. Importantly, we demonstrate that deletion of enhancers and lncRNAs by CRISPR/Cas9 promoted significant changes in VEGFA and VEGFC expression. RNA-seq data from lncRNA deletions showed downstream factors implicated in VEGFA and VEGFC linked pathways, such as angiogenesis and lymphangiogenesis, suggesting functional roles for these lncRNAs. Our study uncovers novel lncRNAs and eRNAs regulating VEGFA and VEGFC that can be targeted to modulate the expression of these important molecules in endothelial cells.

scholarly journals The Role of IL-36 in Infectious Diseases: Potential Target for COVID-19?

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaofang Wang ◽  
Panpan Yi ◽  
Yuejin Liang
Keyword(s):  
Infectious Diseases ◽  
Immune Responses ◽  
Lupus Erythematosus ◽  
Fungal Infections ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Functional Roles ◽  
Cellular Expression ◽  
Inflammatory Bowel

IL-36 is a member of the interleukin 1 cytokine family, which is currently experiencing a renaissance due to the growing understanding of its context-dependent roles and advances in our understanding of the inflammatory response. The immunological role of IL-36 has revealed its profound and indispensable functional roles in psoriasis, as well as in several inflammatory diseases, including inflammatory bowel disease (IBD), systemic lupus erythematosus, rheumatoid arthritis (RA) and cancer. More recently, an increasing body of evidence suggests that IL-36 plays a crucial role in viral, bacterial and fungal infections. There is a growing interest as to whether IL-36 contributes to host protective immune responses against infection as well as the potential implications of IL-36 for the development of new therapeutic strategies. In this review, we summarize the recent progress in understanding cellular expression, regulatory mechanisms and biological roles of IL-36 in infectious diseases, which suggest more specific strategies to maneuver IL-36 as a diagnostic or therapeutic target, especially in COVID-19.

scholarly journals Role of the Tyrosine Phosphatase SHP-2 in Mediating Adrenomedullin Proangiogenic Activity in Solid Tumors

2021 ◽  
Vol 11 ◽  
Author(s):  
Romain Sigaud ◽  
Nadège Dussault ◽  
Caroline Berenguer-Daizé ◽  
Christine Vellutini ◽  
Zohra Benyahia ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Tyrosine Phosphatase ◽  
Vascular Endothelial Cell ◽  
Tumor Vasculature ◽  
Cell Junctions ◽  
Cell Permeability ◽  
Tumor Xenograft ◽  
Dependent Manner

VE-cadherin is an essential adhesion molecule in endothelial adherens junctions, and the integrity of these complexes is thought to be regulated by VE-cadherin tyrosine phosphorylation. We have previously shown that adrenomedullin (AM) blockade correlates with elevated levels of phosphorylated VE-cadherin (pVE-cadherinY731) in endothelial cells, associated with impaired barrier function and a persistent increase in vascular endothelial cell permeability. However, the mechanism underlying this effect is unknown. In this article, we demonstrate that the AM-mediated dephosphorylation of pVE-cadherinY731 takes place through activation of the tyrosine phosphatase SHP-2, as judged by the rise of its active fraction phosphorylated at tyrosine 542 (pSHP-2Y542) in HUVECs and glioblastoma-derived-endothelial cells. Both pre-incubation of HUVECs with SHP-2 inhibitors NSC-87877 and SHP099 and SHP-2 silencing hindered AM-induced dephosphorylation of pVE-cadherinY731 in a dose dependent-manner, showing the role of SHP-2 in the regulation of endothelial cell contacts. Furthermore, SHP-2 inhibition impaired AM-induced HUVECs differentiation into cord-like structures in vitro and impeded AM-induced neovascularization in in vivo Matrigel plugs bioassays. Subcutaneously transplanted U87-glioma tumor xenograft mice treated with AM-receptors-blocking antibodies showed a decrease in pSHP-2Y542 associated with VE-cadherin in nascent tumor vasculature when compared to control IgG-treated xenografts.Our findings show that AM acts on VE-cadherin dynamics through pSHP-2Y542 to finally modulate cell-cell junctions in the angiogenesis process, thereby promoting a stable and functional tumor vasculature.

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