DOCSLIB.ORG

Epha4/Tie2 Crosstalk Regulates Leptomeningeal Collateral Remodeling Following Ischemic Stroke

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Epha4/Tie2 Crosstalk Regulates Leptomeningeal Collateral Remodeling Following Ischemic Stroke EphA4/Tie2 crosstalk regulates leptomeningeal collateral remodeling following ischemic stroke Benjamin Okyere, … , John B. Matson, Michelle H. Theus J Clin Invest. 2019. https://doi.org/10.1172/JCI131493. Research In-Press Preview Neuroscience Vascular biology Leptomeningeal anastomoses or pial collateral vessels play a critical role in cerebral blood flow (CBF) restoration following ischemic stroke. The magnitude of this adaptive response is postulated to be controlled by the endothelium, although the underlying molecular mechanisms remain under investigation. Here we demonstrated that endothelial genetic deletion, using EphA4f/f/Tie2-Cre and EphA4f/f/VeCahderin-CreERT2 mice and vessel painting strategies, implicated EphA4 receptor tyrosine kinase as a major suppressor of pial collateral remodeling, CBF and functional recovery following permanent middle cerebral artery occlusion. Pial collateral remodeling is limited by the cross talk between EphA4-Tie2 signaling in vascular endothelial cells, which is mediated through p-Akt regulation. Furthermore, peptide inhibition of EphA4 resulted in acceleration of the pial arteriogenic response. Our findings demonstrate EphA4 is a negative regulator of Tie2 receptor signaling which limits pial collateral arteriogenesis following cerebrovascular occlusion. Therapeutic targeting of EphA4 and/or Tie2 represents an attractive new strategy for improving collateral function, neural tissue health and functional recovery following ischemic stroke. Find the latest version: https://jci.me/131493/pdf 1 EphA4/Tie2 Crosstalk Regulates Leptomeningeal Collateral Remodeling Following Ischemic Stroke 2 3 Benjamin Okyere1, William A. Mills III4, Xia Wang1, Michael Chen1, Jiang Chen1, Amanda Hazy1, Yun Qian3,6, John B. 4 Matson2,6 and Michelle H. Theus*1,4,5 5 6 1Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA 24061, USA 7 2Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA 8 3Department of Mechanical Engineering, Virginia Tech, Blacksburg VA 24061, USA 9 4School of Neuroscience, Virginia Tech, Blacksburg VA 24061, USA 10 5Center for Regenerative Medicine, VT College of Veterinary Medicine, Blacksburg, Virginia, 24061, USA 11 6Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia, 24061, USA 12 7Graduate Program in Translational Biology, Medicine, and Health, Virginia Tech, Blacksburg, VA 24061 13 14 Running Title: EphA4 negatively regulates collateral remodeling after stroke 15 Keywords: vessel painting, neuroprotection, KYL, angiopoietin-2, tie2 receptor, cerebral blood flow, p-Akt 16 Corresponding author: 17 Michelle H. Theus, Ph.D. 18 Associate Professor 19 Department of Biomedical Sciences and Pathobiology 20 College of Veterinary Medicine, Virginia Tech 21 970 Washington Street SW (MC0910) 22 Blacksburg, VA 24061 23 Tel. 540-231-0909; Fax 540-231-7425; E-mail: [email protected] 24 25 Key words: ischemia, vascular biology, angiopoietin, Tie2 26 27 Abbreviations: VP, vessel painting; pMCAO, permanent middle cerebral artery occlusion; KYL, 28 KYLPYWPVLSSL 29 30 31 Conflict of interest statement: The authors have declared that no conflict of interest exists. 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 1 1 Abstract 2 3 Leptomeningeal anastomoses or pial collateral vessels play a critical role in cerebral blood flow (CBF) restoration 4 following ischemic stroke. The magnitude of this adaptive response is postulated to be controlled by the 5 endothelium, although the underlying molecular mechanisms remain under investigation. Here we demonstrated 6 that endothelial genetic deletion, using EphA4f/f/Tie2-Cre and EphA4f/f/VeCahderin-CreERT2 mice and vessel 7 painting strategies, implicated EphA4 receptor tyrosine kinase as a major suppressor of pial collateral remodeling, 8 CBF and functional recovery following permanent middle cerebral artery occlusion. Pial collateral remodeling 9 is limited by the cross talk between EphA4-Tie2 signaling in vascular endothelial cells, which is mediated through 10 p-Akt regulation. Furthermore, peptide inhibition of EphA4 resulted in acceleration of the pial arteriogenic 11 response. Our findings demonstrate EphA4 is a negative regulator of Tie2 receptor signaling which limits pial 12 collateral arteriogenesis following cerebrovascular occlusion. Therapeutic targeting of EphA4 and/or Tie2 13 represents an attractive new strategy for improving collateral function, neural tissue health and functional 14 recovery following ischemic stroke. 15 16 2 17 Introduction 18 Ischemic stroke results in significant cerebral blood flow (CBF) loss to brain regions predominately served 19 by the middle cerebral artery, leading to cell death and neural tissue dysfunction. However, restoration of CBF 20 may occur through developmentally regulated adaptations to the vascular network called, leptomeningeal 21 anastomoses or pial collateral vessels which provide retrograde reperfusion to vulnerable tissue regions. This 22 phenomenon is essential for preventing or reducing the consequences of an ischemic attack, however, the 23 molecular mechanism(s) regulating the patient-specific pial collateral response remains understudied. While 24 tissue plasminogen activator (tPA) and/or Alteplase remains the gold standard for stroke therapy it is not effective 25 in large vessel occlusions (LVO) or when treatment is started prior to 4.5 hours post-ischemic attack (1, 2) or 9 26 hours in select patients (3). Recently, the use of endovascular thrombectomy has improved outcomes and extended 27 the therapeutic window (4-7). In fact, it has been reported that endovascular thrombectomy has extended the 28 treatment window up to at least 24 hours (8). Extension of this window due to pial collateral-mediated reperfusion 29 enables CBF to maintain tissue protection in the penumbra region. Thus, improving our basic understanding of 30 how collateral vessels remodel will allow us to better diagnose and treat patients with divergent responses. 31 The extent of collateral-mediated reperfusion has a major impact on preserving the penumbra and often 32 dictates stroke outcome (9-13). Several studies have demonstrated that the outcome after thrombolysis and 33 thrombectomy therapy is highly dependent on patient collateral scoring (14-19). Patients with high collateral 34 function also have higher reperfusion rates after rtPA therapy and a lower risk for symptomatic bleeding after 35 reperfusion therapy (20). Pharmacological targeting of the pial collateral network therefore represents a viable 36 therapeutic option to improve outcomes following embolic stroke by sustaining penumbral blood flow and 37 preserving neural tissue health. The middle cerebral arteries (MCA), anterior cerebral arteries (ACA) and 38 posterior cerebral arteries (PCA) anastomose at their distal ends to form the MCA-ACA and MCA-PCA collateral 39 vessels (21). Collateral vessels do not show a proximal-to-distal axis with respect to blood flow rather they 40 connect two arterial branches with opposing flow. Therefore, collateral blood flow is bi-directional along the 41 collateral vessel wall (22). Following an obstruction, collateral vessels undergo immense vascular restructuring 3 42 and remodeling (enlargement), also called arteriogenesis, to allow for uni-directional retrograde blood reperfusion 43 into the area of an occluded arterial branch (22, 23). 44 Although the benefits of targeting the collateral system are evident, further research is essential to 45 elucidate the mechanism(s) underlying this remarkable tissue saving adaptation. Collateral remodeling is initiated 46 when mechanoreceptors on endothelial cells (ECs) detect fluid shear stress after an occlusion (24-26). Thus, the 47 endothelial cells comprised within the collateral niche may perform essential duties during the active remodeling 48 process. Recently, we implicated EphA4 receptor tyrosine kinase in limiting collateral formation and recovery 49 from hindlimb ischemia following femoral artery ligation (FAL) (27). The current study demonstrates that ECs 50 are central to pial collateral remodeling after ischemic stroke and the presence of EphA4 suppresses their growth 51 properties in vitro and in vivo by acting as an inhibitor of the Akt/Tie2 receptor-signaling pathway. These findings 52 greatly improve our understanding of the cellular and molecular mechanism(s) involved in pial collateral 53 remodeling following vascular obstruction. 54 55 Results 56 EphA4f/f/Tie2-Cre knockout (KO) mice show improved CBF, neural tissue and behavioral recovery 57 following pMCAO 58 In the current study, we used EphA4f/f/Tie2-Cre knockout (KO) mice to evaluate changes in cerebral blood flow 59 (CBF) following acute ischemic stroke and subsequent outcomes compared to EphA4f/f wild type (WT) mice. 60 Vascular recombination was confirmed using Tie2-Cre/ROSAmTmG reporter mice (supplemental Fig. 1) and as 61 previously described (27). CBF was measured by Laser Doppler prior to and at 5 minutes (m), 1-4 days (d) post- 62 pMCAO in the ipsilateral hemisphere and the perfusion units quantified and represented relative to baseline pre- 63 injury CBF (Fig. 1A-1B). No significant difference in CBF was observed at 5m post-pMCAO between WT and 64 KO mice (relative PFUs: 0.532 ± 0.026 vs 0.502 ± 0.034). However, we observed a significantly increase in CBF 65 at 1d (0.87 ± 0.05 vs 0.69 ± 0.05), 2d (0.94 ± 0.06 vs 0.73 ± 0.05), 3d (0.95 ± 0.05 vs 0.79 ± 0.06) and 4d (0.97 ± 66 0.04 vs 0.82 ± 0.04) in KO compared to WT mice. These findings correlated
Load more

Recommended publications
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Single-Cell RNA Sequencing Demonstrates the Molecular and Cellular Reprogramming of Metastatic Lung Adenocarcinoma
    ARTICLE https://doi.org/10.1038/s41467-020-16164-1 OPEN Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma Nayoung Kim 1,2,3,13, Hong Kwan Kim4,13, Kyungjong Lee 5,13, Yourae Hong 1,6, Jong Ho Cho4, Jung Won Choi7, Jung-Il Lee7, Yeon-Lim Suh8,BoMiKu9, Hye Hyeon Eum 1,2,3, Soyean Choi 1, Yoon-La Choi6,10,11, Je-Gun Joung1, Woong-Yang Park 1,2,6, Hyun Ae Jung12, Jong-Mu Sun12, Se-Hoon Lee12, ✉ ✉ Jin Seok Ahn12, Keunchil Park12, Myung-Ju Ahn 12 & Hae-Ock Lee 1,2,3,6 1234567890():,; Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell tran- scriptome profiling of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions. 1 Samsung Genome Institute, Samsung Medical Center, Seoul 06351, Korea.
    [Show full text]
  • 4 Transcription and Secretion Novel Regulator of Angiopoietin-Like Protein A
    Acute-Phase Protein α1-Antitrypsin−−A Novel Regulator of Angiopoietin-like Protein 4 Transcription and Secretion This information is current as Eileen Frenzel, Sabine Wrenger, Stephan Immenschuh, of September 28, 2021. Rembert Koczulla, Ravi Mahadeva, H. Joachim Deeg, Charles A. Dinarello, Tobias Welte, A. Mario Q. Marcondes and Sabina Janciauskiene J Immunol 2014; 192:5354-5362; Prepublished online 23 April 2014; Downloaded from doi: 10.4049/jimmunol.1400378 http://www.jimmunol.org/content/192/11/5354 Supplementary http://www.jimmunol.org/content/suppl/2014/04/23/jimmunol.140037 http://www.jimmunol.org/ Material 8.DCSupplemental References This article cites 56 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/192/11/5354.full#ref-list-1 Why The JI? Submit online. by guest on September 28, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Acute-Phase Protein a1-Antitrypsin—A Novel Regulator of Angiopoietin-like Protein 4 Transcription and Secretion Eileen Frenzel,* Sabine Wrenger,* Stephan Immenschuh,† Rembert Koczulla,‡ Ravi Mahadeva,x H.
    [Show full text]
  • Angiocrine Endothelium: from Physiology to Cancer Jennifer Pasquier1,2*, Pegah Ghiabi2, Lotf Chouchane3,4,5, Kais Razzouk1, Shahin Rafi3 and Arash Rafi1,2,3
    Pasquier et al. J Transl Med (2020) 18:52 https://doi.org/10.1186/s12967-020-02244-9 Journal of Translational Medicine REVIEW Open Access Angiocrine endothelium: from physiology to cancer Jennifer Pasquier1,2*, Pegah Ghiabi2, Lotf Chouchane3,4,5, Kais Razzouk1, Shahin Rafi3 and Arash Rafi1,2,3 Abstract The concept of cancer as a cell-autonomous disease has been challenged by the wealth of knowledge gathered in the past decades on the importance of tumor microenvironment (TM) in cancer progression and metastasis. The sig- nifcance of endothelial cells (ECs) in this scenario was initially attributed to their role in vasculogenesis and angiogen- esis that is critical for tumor initiation and growth. Nevertheless, the identifcation of endothelial-derived angiocrine factors illustrated an alternative non-angiogenic function of ECs contributing to both physiological and pathological tissue development. Gene expression profling studies have demonstrated distinctive expression patterns in tumor- associated endothelial cells that imply a bilateral crosstalk between tumor and its endothelium. Recently, some of the molecular determinants of this reciprocal interaction have been identifed which are considered as potential targets for developing novel anti-angiocrine therapeutic strategies. Keywords: Angiocrine, Endothelium, Cancer, Cancer microenvironment, Angiogenesis Introduction of blood vessels in initiation of tumor growth and stated Metastatic disease accounts for about 90% of patient that in the absence of such angiogenesis, tumors can- mortality. Te difculty in controlling and eradicating not expand their mass or display a metastatic phenotype metastasis might be related to the heterotypic interaction [7]. Based on this theory, many investigators assumed of tumor and its microenvironment [1].
    [Show full text]
  • Stromal Cell Interactions Mediated by Hypoxia-Inducible Factors Promote Angiogenesis, Lymphangiogenesis, and Metastasis
    Oncogene (2013) 32, 4057–4063 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc REVIEW Cancer–stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis GL Semenza Interactions between cancer cells and stromal cells, including blood vessel endothelial cells (BECs), lymphatic vessel endothelial cells (LECs), bone marrow-derived angiogenic cells (BMDACs) and other bone marrow-derived cells (BMDCs) play important roles in cancer progression. Intratumoral hypoxia, which affects both cancer and stromal cells, is associated with a significantly increased risk of metastasis and mortality in many human cancers. Recent studies have begun to delineate the molecular mechanisms underlying the effect of intratumoral hypoxia on cancer progression. Reduced O2 availability induces the activity of hypoxia- inducible factors (HIFs), which activate the transcription of target genes encoding proteins that play important roles in many critical aspects of cancer biology. Included among these are secreted factors, including angiopoietin 2, angiopoietin-like 4, placental growth factor, platelet-derived growth factor B, stem cell factor (kit ligand), stromal-derived factor 1, and vascular endothelial growth factor. These factors are produced by hypoxic cancer cells and directly mediate functional interactions with BECs, LECs, BMDACs and other BMDCs that promote angiogenesis, lymphangiogenesis, and metastasis. In addition, lysyl oxidase (LOX) and LOX-like proteins,
    [Show full text]
  • Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance Via Balanced Inhibition of MET, TIE2, and VEGFR2 Bryan D
    Published OnlineFirst August 18, 2015; DOI: 10.1158/1535-7163.MCT-14-1105 Small Molecule Therapeutics Molecular Cancer Therapeutics Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2 Bryan D. Smith1, Michael D. Kaufman1, Cynthia B. Leary1, Benjamin A. Turner1, Scott C. Wise1, Yu Mi Ahn1, R. John Booth1, Timothy M. Caldwell1, Carol L. Ensinger1, Molly M. Hood1, Wei-Ping Lu1, Tristan W. Patt1, William C. Patt1, Thomas J. Rutkoski1, Thiwanka Samarakoon1, Hanumaiah Telikepalli1, Lakshminarayana Vogeti1, Subha Vogeti1, Karen M. Yates1, Lawrence Chun2, Lance J. Stewart2, Michael Clare1, and Daniel L. Flynn1,3 Abstract Altiratinib (DCC-2701) was designed based on the rationale of wild-type and mutated forms, in vitro and in vivo. Through its engineering a single therapeutic agent able to address multiple balanced inhibitory potency versus MET, TIE2, and VEGFR2, hallmarks of cancer (1). Specifically, altiratinib inhibits not only altiratinib provides an agent that inhibits three major evasive mechanisms of tumor initiation and progression, but also drug (re)vascularization and resistance pathways (HGF, ANG, and resistance mechanisms in the tumor and microenvironment VEGF) and blocks tumor invasion and metastasis. Altiratinib through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 exhibits properties amenable to oral administration and exhibits (KDR) kinases. This profile was achieved by optimizing binding substantial blood–brain barrier penetration, an attribute of into the switch control pocket of all three kinases, inducing type II significance for eventual treatment of brain cancers and brain inactive conformations. Altiratinib durably inhibits MET, both metastases. Mol Cancer Ther; 14(9); 1–12.
    [Show full text]
  • Cardiovascular Disease Products
    Cardiovascular Disease Products For more information, visit: www.bosterbio.com Cardiovascular Disease Research Cardiovascular disease is the leading cause of death in developed nations. Boster Bio aims to supply researchers with high-quality antibodies and ELISA kits so they can make new discoveries and help save lives. In this catalogue you will find a comprehensive list of high-affinity Boster antibodies and high sensitivity Boster ELISA kits targeted at proteins associated with cardiovascular disease. Boster: The Fastest Growing About Bosterbio Antibody Company In 2015 Boster is an antibody manufacturer founded in 1993 by histologist Steven Xia. Over the past two decades, Boster and its products have been cited in over 20,000 publications and counting. The firm specializes in developing antibodies and ELISA kits that feature high affinity, Boster Bio received the CitaAb award for high specificity at affordable the greatest increase in number of prices. citations during 2015 than any other antibody manufacturer. Table of Contents Boster Cardiovascular Disease Related Antibodies…………..………..... 2 Boster Cardiovascular Disease Related ELISA Kits……………………..…. 9 1 High Affinity Boster Antibodies Boster supplies only the highest quality antibodies. Our high-affinity polyclonal and monoclonal antibodies are thoroughly validated by Western Blotting, Immunohistochemistry and ELISA. This is our comprehensive catalog of our antibody products related to cardiovascular disease, sorted in alphabetical order by target gene name. Catalog No Product Name
    [Show full text]
  • High Circulating Angiopoietin-2 Levels Exacerbate Pulmonary
    Thorax Online First, published on September 25, 2017 as 10.1136/thoraxjnl-2017-210413 Pulmonary vasculature Thorax: first published as 10.1136/thoraxjnl-2017-210413 on 25 September 2017. Downloaded from ORIGINAL artiCLE High circulating angiopoietin-2 levels exacerbate pulmonary inflammation but not vascular leak or mortality in endotoxin-induced lung injury in mice Kenny Schlosser,1 Mohamad Taha,1,2 Yupu Deng,1 Lauralyn A McIntyre,3 Shirley H J Mei,1 Duncan J Stewart1,2,4 ► Additional material is ABSTRACT published online only. To view Background Elevated plasma levels of angiopoietin-2 Key messages please visit the journal online (http:// dx. doi. org/ 10. 1136/ (ANGPT2) have been reported in patients with acute thoraxjnl- 2017- 210413). lung injury (ALI); however, it remains unclear whether What is the key question? this increase contributes to, or just marks, the underlying ► Elevated plasma levels of angiopoietin-2 1Regenerative Medicine vasculopathic inflammation and leak associated with (ANGPT2) in acute lung injury (ALI)/acute Program, Ottawa Hospital ALI. Here we investigated the biological consequences respiratory distress syndrome patients are Research Institute , University associated with poor prognosis; however, of Ottawa, Ottawa, Ontario, of inducing high circulating levels of ANGPT2 in a mouse Canada model of endotoxin-induced ALI. it remains unclear whether these elevated 2Department of Cellular and Methods Transgenic mice (ANGPT2OVR) with elevated circulating levels are just a marker or mediator Molecular Medicine, University circulating levels of ANGPT2, achieved through of underlying pulmonary vascular dysfunction. of Ottawa, Ottawa, Ontario, conditional hepatocyte-specific overexpression, Canada What is the bottom line? 3 were examined from 3 to 72 hours following Clinical Epidemiology Program, ► For the first time, this study demonstrates Ottawa Hospital Research lipopolysaccharide (LPS)-induced ALI.
    [Show full text]
  • Role of EFNB2/EPHB4 Signaling in Spiral Artery Development During Pregnancy: an Appraisal
    ESSAY Molecular Reproduction & Development 83:12–18 (2016) Role of EFNB2/EPHB4 Signaling in Spiral Artery Development During Pregnancy: An Appraisal HONGMEI DONG,* CHAORAN YU, JIAO MU, JI ZHANG, AND WEI LIN Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China SUMMARY EFNB2 and EPHB4, which belong to a large tyrosine kinase receptor superfamily, are molecular markers of arterial and venous blood vessels, respectively. EFNB2/ EPHB4 signaling plays an important role in physiological and pathological angiogen- esis, and its role in tumor vessel development has been extensively studied. [W]e hypothesize that changing Pregnancy and tumors share similar features, including continuous cell proliferation the distinct spatiotemporal and increased demand for a blood supply. Our previous studies showed that Efnb2 expression of EFNB2/ Ephb4 and were expressed dynamically in the spiral arteries, uterine natural killer EPHB4...contributes to spiral À cells, and trophoblasts during mouse gestation Days 6.5 12.5. Moreover, uterine artery remodeling. natural killer cells and trophoblasts are required for the modification of spiral arteries. Oxygen tension within the pregnant uterus, which contributes to the vascular development, also affects EFNB2 and EPHB4 expression. Considering the role of ÃCorresponding author: EFNB2/EPHB4 signaling in embryonic and tumor vascular development, and its Department of Forensic Medicine Tongji Medical College of dynamic expression in the decidua and placenta, we hypothesize that EFNB2 and Huazhong University of EPHB4 are involved in the regulation of spiral artery remodeling. Investigating this Science and Technology hypothesis will help clarify the mechanisms of pathological pregnancy that may 13 Hangkong Road Wuhan, Hubei 430030, P.
    [Show full text]
  • Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Bevacizumab in Breast Cancer Patients
    RESEARCH ARTICLE Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Bevacizumab in Breast Cancer Patients Issam Makhoul1*, Valentina K. Todorova2, Eric R. Siegel3, Stephen W. Erickson3, a1111111111 Ishwori Dhakal3, Vinay R. Raj2, Jeannette Y. Lee3, Mohammed S. Orloff4, Robert J. Griffin5, a1111111111 Ronda S. Henry-Tillman6, Suzanne Klimberg6,7, Laura F. Hutchins1, Susan A. Kadlubar5 a1111111111 a1111111111 1 Division of Hematology/Oncology Division, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America, 2 Division of Medical Genetics, University of Arkansas for Medical a1111111111 Sciences, Little Rock, Arkansas, United States of America, 3 Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America, 4 Department of Epidemiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America, 5 Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America, 6 Division of Breast Surgical Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America, 7 Department of Pathology, University of OPEN ACCESS Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America Citation: Makhoul I, Todorova VK, Siegel ER, Erickson SW, Dhakal I, Raj VR, et al. (2017) * [email protected] Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Abstract Bevacizumab in Breast Cancer Patients. PLoS ONE 12(1): e0168550. doi:10.1371/journal. pone.0168550 Background Editor: Ratna B. Ray, Saint Louis University, UNITED STATES We previously reported improved pathologic complete response (pCR) in a prospective Received: August 14, 2016 phase II study using neoadjuvant bevacizumab in combination with chemotherapy com- pared to chemotherapy alone in breast cancer patients (41% vs.
    [Show full text]
  • Epigenetic Mechanisms Are Involved in the Oncogenic Properties of ZNF518B in Colorectal Cancer
    Epigenetic mechanisms are involved in the oncogenic properties of ZNF518B in colorectal cancer Francisco Gimeno-Valiente, Ángela L. Riffo-Campos, Luis Torres, Noelia Tarazona, Valentina Gambardella, Andrés Cervantes, Gerardo López-Rodas, Luis Franco and Josefa Castillo SUPPLEMENTARY METHODS 1. Selection of genomic sequences for ChIP analysis To select the sequences for ChIP analysis in the five putative target genes, namely, PADI3, ZDHHC2, RGS4, EFNA5 and KAT2B, the genomic region corresponding to the gene was downloaded from Ensembl. Then, zoom was applied to see in detail the promoter, enhancers and regulatory sequences. The details for HCT116 cells were then recovered and the target sequences for factor binding examined. Obviously, there are not data for ZNF518B, but special attention was paid to the target sequences of other zinc-finger containing factors. Finally, the regions that may putatively bind ZNF518B were selected and primers defining amplicons spanning such sequences were searched out. Supplementary Figure S3 gives the location of the amplicons used in each gene. 2. Obtaining the raw data and generating the BAM files for in silico analysis of the effects of EHMT2 and EZH2 silencing The data of siEZH2 (SRR6384524), siG9a (SRR6384526) and siNon-target (SRR6384521) in HCT116 cell line, were downloaded from SRA (Bioproject PRJNA422822, https://www.ncbi. nlm.nih.gov/bioproject/), using SRA-tolkit (https://ncbi.github.io/sra-tools/). All data correspond to RNAseq single end. doBasics = TRUE doAll = FALSE $ fastq-dump -I --split-files SRR6384524 Data quality was checked using the software fastqc (https://www.bioinformatics.babraham. ac.uk /projects/fastqc/). The first low quality removing nucleotides were removed using FASTX- Toolkit (http://hannonlab.cshl.edu/fastxtoolkit/).
    [Show full text]
  • Angiopoietin/Tie2 Axis Regulates the Age-At-Injury Cerebrovascular Response to Traumatic Brain Injury
    9618 • The Journal of Neuroscience, November 7, 2018 • 38(45):9618–9634 Development/Plasticity/Repair Angiopoietin/Tie2 Axis Regulates the Age-at-Injury Cerebrovascular Response to Traumatic Brain Injury Thomas R. Brickler,1* Amanda Hazy,1* Fernanda Guilhaume Correa,2 Rujuan Dai,1 Elizabeth J.A. Kowalski,1 Ross Dickerson,3 Jiang Chen,1 Xia Wang,1 Paul D. Morton,1 Abby Whittington,3 Ansar Ahmed,1 and XMichelle H. Theus1 1The Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, 2Translational Biology, Medicine, and Health Graduate Program, School of Medicine, and 3Department of Chemical Engineering, School of Biomedical Engineering and Sciences, Virginia Polytechnic Institute and State University, Roanoke, Virginia 24061 Although age-at-injury influences chronic recovery from traumatic brain injury (TBI), the differential effects of age on early outcome remainunderstudied.Usingamalemurinemodelofmoderatecontusioninjury,weinvestigatedtheunderlyingmechanism(s)regulating the distinct response between juvenile and adult TBI. We demonstrate similar biomechanical and physical properties of naive juvenile and adult brains. However, following controlled cortical impact (CCI), juvenile mice displayed reduced cortical lesion formation, cell death, and behavioral deficits at 4 and 14 d. Analysis of high-resolution laser Doppler imaging showed a similar loss of cerebral blood flow (CBF) in the ipsilateral cortex at 3 and 24 h post-CCI, whereas juvenile mice showed enhanced subsequent restoration at 2–4 d compared with adults. These findings correlated with reduced blood–brain barrier (BBB) disruption and increased perilesional vessel density. To address whether an age-dependent endothelial cell (EC) response affects vessel stability and tissue outcome, we magnetically isolated CD31 ϩ ECs from sham and injured cortices and evaluated mRNA expression.
    [Show full text]