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https://www.readbyqxmd.com/read/28925392/atypical-e2fs-inhibit-tumor-angiogenesis
#1
B G M W Weijts, B Westendorp, B T Hien, L M Martínez-López, M Zijp, I Thurlings, R E Thomas, S Schulte-Merker, W J Bakker, A de Bruin
Atypical E2F transcription factors (E2F7 and E2F8) function as key regulators of cell cycle progression and their inactivation leads to spontaneous cancer formation in mice. However, the mechanism of the tumor suppressor functions of E2F7/8 remain obscure. In this study we discovered that atypical E2Fs control tumor angiogenesis, one of the hallmarks of cancer. We genetically inactivated atypical E2Fs in epithelial and mesenchymal neoplasm and analyzed blood vessel formation in three different animal models of cancer...
September 18, 2017: Oncogene
https://www.readbyqxmd.com/read/28924218/uncontrolled-angiogenic-precursor-expansion-causes-coronary-artery-anomalies-in-mice-lacking-pofut1
#2
Yidong Wang, Bingruo Wu, Pengfei Lu, Donghong Zhang, Brian Wu, Shweta Varshney, Gonzalo Del Monte-Nieto, Zhenwu Zhuang, Rabab Charafeddine, Adam H Kramer, Nicolas E Sibinga, Nikolaos G Frangogiannis, Richard N Kitsis, Ralf H Adams, Kari Alitalo, David J Sharp, Richard P Harvey, Pamela Stanley, Bin Zhou
Coronary artery anomalies may cause life-threatening cardiac complications; however, developmental mechanisms underpinning coronary artery formation remain ill-defined. Here we identify an angiogenic cell population for coronary artery formation in mice. Regulated by a DLL4/NOTCH1/VEGFA/VEGFR2 signaling axis, these angiogenic cells generate mature coronary arteries. The NOTCH modulator POFUT1 critically regulates this signaling axis. POFUT1 inactivation disrupts signaling events and results in excessive angiogenic cell proliferation and plexus formation, leading to anomalous coronary arteries, myocardial infarction and heart failure...
September 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28923397/the-two-novel-dll4-targeting-antibody-drug-conjugates-mvm03-and-mgd03-show-potent-anti-tumour-activity-in-breast-cancer-xenograft-models
#3
Shijing Wang, Rihong Zhou, Fumou Sun, Renjie Li, Min Wang, Min Wu
The anti-human Delta-like 4 (DLL4) monoclonal antibody MMGZ01 has a high affinity to hrDLL4 and arrests the DLL4-mediated human umbilical vein endothelial cell (HUVEC) phenotype, promotes immature vessels, and effectively reduces breast cancer cell growth in vivo. To develop a much more effective therapy, we conjugated MMGZ01 with two small-molecule cytotoxic agents, i.e., monomethyl auristatin E (MMAE) and doxorubicin (DOX), with different linkers to generate antibody-drug conjugates (ADCs), i.e., MMGZ01-vc-MMAE (named MvM03) and MMGZ01-GMBS-DOX (named MGD03), that are more potent therapeutic agents than naked antibody therapeutic agents...
September 15, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28846711/identification-of-novel-biomarkers-to-monitor-%C3%AE-cell-function-and-enable-early-detection-of-type-2-diabetes-risk
#4
Kirstine J Belongie, Ele Ferrannini, Kjell Johnson, Patricia Andrade-Gordon, Michael K Hansen, John R Petrie
A decline in β-cell function is a prerequisite for the development of type 2 diabetes, yet the level of β-cell function in individuals at risk of the condition is rarely measured. This is due, in part, to the fact that current methods for assessing β-cell function are inaccurate, prone to error, labor-intensive, or affected by glucose-lowering therapy. The aim of the current study was to identify novel circulating biomarkers to monitor β-cell function and to identify individuals at high risk of developing β-cell dysfunction...
2017: PloS One
https://www.readbyqxmd.com/read/28839276/corrigendum-novel-missense-mutation-in-dll4-in-a-japanese-sporadic-case-of-adams-oliver-syndrome
#5
Miwako Nagasaka, Mariko Taniguchi-Ikeda, Hidehito Inagaki, Yuya Ouchi, Daisuke Kurokawa, Keiji Yamana, Risa Harada, Kandai Nozu, Yoshitada Sakai, Sushil K Mishra, Yoshiki Yamaguchi, Ichiro Morioka, Tatsushi Toda, Hiroki Kurahashi, Kazumoto Iijima
This corrects the article DOI: 10.1038/jhg.2017.48.
September 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/28819706/generation-of-a-functional-humanized-delta-like-ligand-4-transgenic-mouse-model
#6
John Wiseman, Pernilla Gregersson, Johan Johansson, Kerstin Magnell, Fernanda Pilataxi, Chris Morehouse, Philip Brohawn, Nicholas Holoweckyj, Patrick Strout, Song Cho
Humanized mouse models are important tools in many areas of biological drug development including, within oncology research, the development of antagonistic antibodies that have the potential to block tumor growth by controlling vascularization and are key to the generation of in vivo proof-of-concept efficacy data. However, due to cross reactivity between human antibodies and mouse target such studies regularly require mouse models expressing only the human version of the target molecule. Such humanized knock-in/knock-out, KIKO, models are dependent upon the generation of homozygous mice expressing only the human molecule, compensating for loss of the mouse form...
August 17, 2017: Transgenic Research
https://www.readbyqxmd.com/read/28812183/anti-dll4-antibody-inhibits-the-differentiation-of-th17-cells-in-asthmatic-mice
#7
Cuiye Weng, Lei Chong, Xiaoxiao Jia, Rongying Zheng, Yue Huang, Tingting Zhu, Changchong Li, Weixi Zhang
T helper 17 (Th17) cells play an important role in allergic asthma, and the Notch ligand Delta-like ligand (Dll)4 has been reported to direct the differentiation of Th17 cells. In this study, experimental animals were divided into five groups (control group, asthma group, physiological saline group, anti-Dll4 antibody group, and immunoglobulin G group). The study aimed to explore the effect of anti-Dll4 antibody on the differentiation of Th17 cell in asthmatic mice. Dll4 protein expressions were performed by immunohistochemical imaging...
August 15, 2017: Inflammation
https://www.readbyqxmd.com/read/28791758/agent-based-computational-model-of-retinal-angiogenesis-simulates-microvascular-network-morphology-as-a-function-of-pericyte-coverage
#8
Joseph Walpole, Feilim Mac Gabhann, Shayn M Peirce, John C Chappell
OBJECTIVE: Define a role for perivascular cells during developmental retinal angiogenesis in the context of endothelial cell Notch1-DLL4 signaling at the multicellular network level. METHODS: The retinal vasculature is highly sensitive to growth factor mediated intercellular signaling. Although endothelial cell signaling has been explored in detail, it remains unclear how pericytes function to modulate these signals that lead to a diverse set of vascular network patterns in health and disease...
August 8, 2017: Microcirculation: the Official Journal of the Microcirculatory Society, Inc
https://www.readbyqxmd.com/read/28776666/potential-role-of-the-jagged1-notch1-signaling-pathway-in-the-endothelial-myofibroblast-transition-during-blm-induced-pulmonary-fibrosis
#9
Qian Yin, Weihua Wang, Guangbin Cui, Linfeng Yan, Song Zhang
Endothelial cell myofibroblast transition (EndoMT) is found during the process of bleomycin (BLM)-induced pulmonary fibrosis in rats, and plays a very important role in sustaining inflammation and collagen secretion. Moreover, some studies have suggested that the Notch1 signaling pathway may be involved in the expression of α-smooth muscle actin (α-SMA) in pulmonary microvascular endothelial cells (PMVECs), a protein marker of EndoMT. Therefore, we aimed to investigate the expression level of α-SMA and Notch1-related signaling molecules in PMVECs from BLM-induced rats and determine the relationship between the Notch1 signaling pathway and the expression of α-SMA in PMVECs...
August 4, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28760777/sumoylation-negatively-regulates-angiogenesis-by-targeting-endothelial-notch-signaling
#10
Xiaolong Zhu, Sha Ding, Cong Qiu, Yanna Shi, Lin Song, Yueyue Wang, Yuewen Wang, Jinying Li, Yiran Wang, Yi Sun, Lingfeng Qin, Jun Chen, Michael Simons, Wang Min, Luyang Yu
RATIONALE: The highly conserved NOTCH (neurogenic locus notch homolog protein) signaling pathway functions as a key cell-cell interaction mechanism controlling cell fate and tissue patterning, whereas its dysregulation is implicated in a variety of developmental disorders and cancers. The pivotal role of endothelial NOTCH in regulation of angiogenesis is widely appreciated; however, little is known about what controls its signal transduction. Our previous study indicated the potential role of post-translational SUMO (small ubiquitin-like modifier) modification (SUMOylation) in vascular disorders...
September 1, 2017: Circulation Research
https://www.readbyqxmd.com/read/28733457/role-of-bone-morphogenetic-proteins-in-sprouting-angiogenesis-differential-bmp-receptor-dependent-signaling-pathways-balance-stalk-vs-tip-cell-competence
#11
Andreas Benn, Christian Hiepen, Marc Osterland, Christof Schütte, An Zwijsen, Petra Knaus
Before the onset of sprouting angiogenesis, the endothelium is prepatterned for the positioning of tip and stalk cells. Both cell identities are not static, as endothelial cells (ECs) constantly compete for the tip cell position in a dynamic fashion. Here, we show that both bone morphogenetic protein (BMP) 2 and BMP6 are proangiogenic in vitro and ex vivo and that the BMP type I receptors, activin receptor-like kinase (ALK)3 and ALK2, play crucial and distinct roles in this process. BMP2 activates the expression of tip cell-associated genes, such as DLL4 (delta-like ligand 4) and KDR (kinase insert domain receptor), and p38-heat shock protein 27 (HSP27)-dependent cell migration, thereby generating tip cell competence...
July 21, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28714969/endothelial-notch-signalling-limits-angiogenesis-via-control-of-artery-formation
#12
Sana S Hasan, Roman Tsaryk, Martin Lange, Laura Wisniewski, John C Moore, Nathan D Lawson, Karolina Wojciechowska, Hans Schnittler, Arndt F Siekmann
Angiogenic sprouting needs to be tightly controlled. It has been suggested that the Notch ligand dll4 expressed in leading tip cells restricts angiogenesis by activating Notch signalling in trailing stalk cells. Here, we show using live imaging in zebrafish that activation of Notch signalling is rather required in tip cells. Notch activation initially triggers expression of the chemokine receptor cxcr4a. This allows for proper tip cell migration and connection to the pre-existing arterial circulation, ultimately establishing functional arterial-venous blood flow patterns...
August 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28714968/dll4-and-notch-signalling-couples-sprouting-angiogenesis-and-artery-formation
#13
Mara E Pitulescu, Inga Schmidt, Benedetto Daniele Giaimo, Tobiah Antoine, Frank Berkenfeld, Francesca Ferrante, Hongryeol Park, Manuel Ehling, Daniel Biljes, Susana F Rocha, Urs H Langen, Martin Stehling, Takashi Nagasawa, Napoleone Ferrara, Tilman Borggrefe, Ralf H Adams
Endothelial sprouting and proliferation are tightly coordinated processes mediating the formation of new blood vessels during physiological and pathological angiogenesis. Endothelial tip cells lead sprouts and are thought to suppress tip-like behaviour in adjacent stalk endothelial cells by activating Notch. Here, we show with genetic experiments in postnatal mice that the level of active Notch signalling is more important than the direct Dll4-mediated cell-cell communication between endothelial cells. We identify endothelial expression of VEGF-A and of the chemokine receptor CXCR4 as key processes controlling Notch-dependent vessel growth...
August 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28711779/hyperactive-foxo1-results-in-lack-of-tip-stalk-identity-and-deficient-microvascular-regeneration-during-kidney-injury
#14
Lan T H Dang, Takahide Aburatani, Graham A Marsh, Bryce G Johnson, Stella Alimperti, Christine J Yoon, Angela Huang, Suzanne Szak, Naoki Nakagawa, Ivan Gomez, Shuyu Ren, Sarah K Read, Chris Sparages, Alfred C Aplin, Roberto F Nicosia, Chris Chen, Giovanni Ligresti, Jeremy S Duffield
Loss of the microvascular (MV) network results in tissue ischemia, loss of tissue function, and is a hallmark of chronic diseases. The incorporation of a functional vascular network with that of the host remains a challenge to utilizing engineered tissues in clinically relevant therapies. We showed that vascular-bed-specific endothelial cells (ECs) exhibit differing angiogenic capacities, with kidney microvascular endothelial cells (MVECs) being the most deficient, and sought to explore the underlying mechanism...
October 2017: Biomaterials
https://www.readbyqxmd.com/read/28695891/the-endothelial-transcription-factor-erg-mediates-angiopoietin-1-dependent-control-of-notch-signalling-and-vascular-stability
#15
A V Shah, G M Birdsey, C Peghaire, M E Pitulescu, N P Dufton, Y Yang, I Weinberg, L Osuna Almagro, L Payne, J C Mason, H Gerhardt, R H Adams, A M Randi
Notch and Angiopoietin-1 (Ang1)/Tie2 pathways are crucial for vascular maturation and stability. Here we identify the transcription factor ERG as a key regulator of endothelial Notch signalling. We show that ERG controls the balance between Notch ligands by driving Delta-like ligand 4 (Dll4) while repressing Jagged1 (Jag1) expression. In vivo, this regulation occurs selectively in the maturing plexus of the mouse developing retina, where Ang1/Tie2 signalling is active. We find that ERG mediates Ang1-dependent regulation of Notch ligands and is required for the stabilizing effects of Ang1 in vivo...
July 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/28656980/neurovascular-egfl7-regulates-adult-neurogenesis-in-the-subventricular-zone-and-thereby-affects-olfactory-perception
#16
Frank Bicker, Verica Vasic, Guilherme Horta, Felipe Ortega, Hendrik Nolte, Atria Kavyanifar, Stefanie Keller, Nevenka Dudvarski Stankovic, Patrick N Harter, Rui Benedito, Beat Lutz, Tobias Bäuerle, Jens Hartwig, Jan Baumgart, Marcus Krüger, Konstantin Radyushkin, Lavinia Alberi, Benedikt Berninger, Mirko H H Schmidt
Adult neural stem cells reside in a specialized niche in the subventricular zone (SVZ). Throughout life they give rise to adult-born neurons in the olfactory bulb (OB), thus contributing to neural plasticity and pattern discrimination. Here, we show that the neurovascular protein EGFL7 is secreted by endothelial cells and neural stem cells (NSCs) of the SVZ to shape the vascular stem-cell niche. Loss of EGFL7 causes an accumulation of activated NSCs, which display enhanced activity and re-entry into the cell cycle...
June 28, 2017: Nature Communications
https://www.readbyqxmd.com/read/28648028/-expression-changes-of-notch-and-nuclear-factor-%C3%AE%C2%BAb-signaling-pathways-in-the-rat-heart-with-myocardial-infarction
#17
J L Jin, Z T Deng, R G Lyu, X H Liu, J R Wei
Objective: To observe the expression changes of Notch and nuclear factor-κB (NF-κB) signaling pathways in rat myocardium post myocardial infarction. Methods: Myocardial infarction was established by ligation of the left anterior descending coronary artery(MI group), sham rats (similar surgical procedure without coronary artery ligation) served as control, the rats were sacrificed at first week, 4th and 8th week after operation, the non-infarct myocardial tissue in both groups was obtained to detect the mRNA expression of Notch1, Dll4 and Hes1 by RT-PCR, the protein expression of NICD1 was detected by Western blot, the nuclear protein p65 content was detected to reflect the activation degree of NF-κB signaling in the cardiomyocytes...
June 24, 2017: Zhonghua Xin Xue Guan Bing za Zhi
https://www.readbyqxmd.com/read/28623973/dynamic-maternal-and-fetal-notch-activity-and-expression-in-placentation
#18
Heather I Levin, Chantae S Sullivan-Pyke, Virginia E Papaioannou, Ronald J Wapner, Jan K Kitajewski, Carrie J Shawber, Nataki C Douglas
INTRODUCTION: Murine placentation requires trophoblast Notch2, while the Notch ligand, JAGGED1, is reduced in invasive trophoblasts from women with preeclampsia. However, the placental cells with active Notch signaling and expression of other Notch proteins and ligands in placentation have yet to be defined. We sought to identify endothelial cell and trophoblast subtypes with canonical Notch signaling in the decidua and placenta and correlate this to expression of Notch proteins and ligands...
July 2017: Placenta
https://www.readbyqxmd.com/read/28599454/differential-expression-of-the-notch1-receptor-and-its-ligands-dll1-dll3-and-dll4-in-distinct-human-pituitary-adenoma-subtypes
#19
Jianfu Zhang, Hua Gao, Yazhuo Zhang
Pituitary adenoma (PA) is a common type of benign tumor of the pituitary gland that is characterized by specific signs and symptoms, primarily associated with hypersecretion of pituitary glycoprotein hormones (thyroid-stimulating, growth and adrenocorticotrophic hormones, and prolactin). Surgery is the first-line treatment, although postoperative residual tissues/cells and subsequent recurrence remain notable complications. Gene therapy is an effective approach for treatment, as previous studies have demonstrated that the Notch signaling pathway participates in the pathogenesis of PA...
June 2017: Oncology Letters
https://www.readbyqxmd.com/read/28567545/host-genetic-modifiers-of-nonproductive-angiogenesis-inhibit-breast-cancer
#20
Michael J Flister, Shirng-Wern Tsaih, Alexander Stoddard, Cody Plasterer, Jaidip Jagtap, Abdul K Parchur, Gayatri Sharma, Anthony R Prisco, Angela Lemke, Dana Murphy, Mona Al-Gizawiy, Michael Straza, Sophia Ran, Aron M Geurts, Melinda R Dwinell, Andrew S Greene, Carmen Bergom, Peter S LaViolette, Amit Joshi
PURPOSE: Multiple aspects of the tumor microenvironment (TME) impact breast cancer, yet the genetic modifiers of the TME are largely unknown, including those that modify tumor vascular formation and function. METHODS: To discover host TME modifiers, we developed a system called the Consomic/Congenic Xenograft Model (CXM). In CXM, human breast cancer cells are orthotopically implanted into genetically engineered consomic xenograft host strains that are derived from two parental strains with different susceptibilities to breast cancer...
May 31, 2017: Breast Cancer Research and Treatment
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