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1
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Larionov A, Hammer CM, Fiedler K, Filgueira L. Dynamics of Endothelial Cell Diversity and Plasticity in Health and Disease. Cells 2024; 13:1276. [PMID: 39120307 PMCID: PMC11312403 DOI: 10.3390/cells13151276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 07/19/2024] [Accepted: 07/19/2024] [Indexed: 08/10/2024] Open
Abstract
Endothelial cells (ECs) are vital structural units of the cardiovascular system possessing two principal distinctive properties: heterogeneity and plasticity. Endothelial heterogeneity is defined by differences in tissue-specific endothelial phenotypes and their high predisposition to modification along the length of the vascular bed. This aspect of heterogeneity is closely associated with plasticity, the ability of ECs to adapt to environmental cues through the mobilization of genetic, molecular, and structural alterations. The specific endothelial cytoarchitectonics facilitate a quick structural cell reorganization and, furthermore, easy adaptation to the extrinsic and intrinsic environmental stimuli, known as the epigenetic landscape. ECs, as universally distributed and ubiquitous cells of the human body, play a role that extends far beyond their structural function in the cardiovascular system. They play a crucial role in terms of barrier function, cell-to-cell communication, and a myriad of physiological and pathologic processes. These include development, ontogenesis, disease initiation, and progression, as well as growth, regeneration, and repair. Despite substantial progress in the understanding of endothelial cell biology, the role of ECs in healthy conditions and pathologies remains a fascinating area of exploration. This review aims to summarize knowledge and concepts in endothelial biology. It focuses on the development and functional characteristics of endothelial cells in health and pathological conditions, with a particular emphasis on endothelial phenotypic and functional heterogeneity.
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Affiliation(s)
- Alexey Larionov
- Faculty of Science and Medicine, Anatomy, University of Fribourg, Route Albert-Gockel 1, CH-1700 Fribourg, Switzerland; (C.M.H.); (L.F.)
| | - Christian Manfred Hammer
- Faculty of Science and Medicine, Anatomy, University of Fribourg, Route Albert-Gockel 1, CH-1700 Fribourg, Switzerland; (C.M.H.); (L.F.)
| | - Klaus Fiedler
- Independent Researcher, CH-1700 Fribourg, Switzerland;
| | - Luis Filgueira
- Faculty of Science and Medicine, Anatomy, University of Fribourg, Route Albert-Gockel 1, CH-1700 Fribourg, Switzerland; (C.M.H.); (L.F.)
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Brouillard P, Murtomäki A, Leppänen VM, Hyytiäinen M, Mestre S, Potier L, Boon LM, Revencu N, Greene A, Anisimov A, Salo MH, Hinttala R, Eklund L, Quéré I, Alitalo K, Vikkula M. Loss-of-function mutations of the TIE1 receptor tyrosine kinase cause late-onset primary lymphedema. J Clin Invest 2024; 134:e173586. [PMID: 38820174 PMCID: PMC11245153 DOI: 10.1172/jci173586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 05/24/2024] [Indexed: 06/02/2024] Open
Abstract
Primary lymphedema (PL), characterized by tissue swelling, fat accumulation, and fibrosis, results from defects in lymphatic vessels or valves caused by mutations in genes involved in development, maturation, and function of the lymphatic vascular system. Pathogenic variants in various genes have been identified in about 30% of PL cases. By screening of a cohort of 755 individuals with PL, we identified two TIE1 (tyrosine kinase with immunoglobulin- and epidermal growth factor-like domains 1) missense variants and one truncating variant, all predicted to be pathogenic by bioinformatic algorithms. The TIE1 receptor, in complex with TIE2, binds angiopoietins to regulate the formation and remodeling of blood and lymphatic vessels. The premature stop codon mutant encoded an inactive truncated extracellular TIE1 fragment with decreased mRNA stability, and the amino acid substitutions led to decreased TIE1 signaling activity. By reproducing the two missense variants in mouse Tie1 via CRISPR/Cas9, we showed that both cause edema and are lethal in homozygous mice. Thus, our results indicate that TIE1 loss-of-function variants can cause lymphatic dysfunction in patients. Together with our earlier demonstration that ANGPT2 loss-of-function mutations can also cause PL, our results emphasize the important role of the ANGPT2/TIE1 pathway in lymphatic function.
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Affiliation(s)
- Pascal Brouillard
- Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium
| | - Aino Murtomäki
- Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland
- Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Veli-Matti Leppänen
- Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland
- Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Marko Hyytiäinen
- Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland
- Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Sandrine Mestre
- Department of Vascular Medicine, Centre de Référence des Maladies Lymphatiques et Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, France
| | - Lucas Potier
- Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium
| | - Laurence M. Boon
- Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium
- Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, VASCERN-VASCA Reference Centre, Brussels, Belgium
| | - Nicole Revencu
- Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium
| | - Arin Greene
- Department of Plastic and Oral Surgery, Lymphedema Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Andrey Anisimov
- Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland
- Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Miia H. Salo
- Biocenter Oulu, Research Unit of Clinical Medicine and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Reetta Hinttala
- Biocenter Oulu, Research Unit of Clinical Medicine and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Lauri Eklund
- Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Isabelle Quéré
- Department of Vascular Medicine, Centre de Référence des Maladies Lymphatiques et Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, France
| | - Kari Alitalo
- Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland
- Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Miikka Vikkula
- Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium
- WELBIO department, WEL Research Institute, Wavre, Belgium
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3
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Du J, Liu P, Zhou Y, Misener S, Sharma I, Leeaw P, Thomson BR, Jin J, Quaggin SE. The mechanosensory channel PIEZO1 functions upstream of angiopoietin/TIE/FOXO1 signaling in lymphatic development. J Clin Invest 2024; 134:e176577. [PMID: 38747287 PMCID: PMC11093609 DOI: 10.1172/jci176577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 03/12/2024] [Indexed: 05/19/2024] Open
Abstract
Lymphedema is a debilitating disease with no effective cure and affects an estimated 250 million individuals worldwide. Prior studies have identified mutations in piezo-type mechanosensitive ion channel component 1 (PIEZO1), angiopoietin 2 (ANGPT2), and tyrosine kinase with Ig-like and EGF-like domains 1 (TIE1) in patients with primary lymphedema. Here, we identified crosstalk between these molecules and showed that activation of the mechanosensory channel PIEZO1 in lymphatic endothelial cells (LECs) caused rapid exocytosis of the TIE ligand ANGPT2, ectodomain shedding of TIE1 by disintegrin and metalloproteinase domain-containing protein 17 (ADAM17), and increased TIE/PI3K/AKT signaling, followed by nuclear export of the transcription factor FOXO1. These data establish a functional network between lymphedema-associated genes and provide what we believe to be the first molecular mechanism bridging channel function with vascular signaling and intracellular events culminating in transcriptional regulation of genes expressed in LECs. Our study provides insights into the regulation of lymphatic function and molecular pathways involved in human disease.
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Affiliation(s)
- Jing Du
- Feinberg Cardiovascular and Renal Research Institute
| | - Pan Liu
- Feinberg Cardiovascular and Renal Research Institute
| | - Yalu Zhou
- Feinberg Cardiovascular and Renal Research Institute
| | - Sol Misener
- Feinberg Cardiovascular and Renal Research Institute
| | - Isha Sharma
- Feinberg Cardiovascular and Renal Research Institute
| | - Phoebe Leeaw
- Feinberg Cardiovascular and Renal Research Institute
| | - Benjamin R. Thomson
- Feinberg Cardiovascular and Renal Research Institute
- Department of Ophthalmology, and
| | - Jing Jin
- Feinberg Cardiovascular and Renal Research Institute
- Division of Nephrology, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Susan E. Quaggin
- Feinberg Cardiovascular and Renal Research Institute
- Division of Nephrology, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
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Morooka N, Gui N, Ando K, Sako K, Fukumoto M, Hasegawa U, Hußmann M, Schulte-Merker S, Mochizuki N, Nakajima H. Angpt1 binding to Tie1 regulates the signaling required for lymphatic vessel development in zebrafish. Development 2024; 151:dev202269. [PMID: 38742432 DOI: 10.1242/dev.202269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 04/26/2024] [Indexed: 05/16/2024]
Abstract
Development of the vascular system is regulated by multiple signaling pathways mediated by receptor tyrosine kinases. Among them, angiopoietin (Ang)/Tie signaling regulates lymphatic and blood vessel development in mammals. Of the two Tie receptors, Tie2 is well known as a key mediator of Ang/Tie signaling, but, unexpectedly, recent studies have revealed that the Tie2 locus has been lost in many vertebrate species, whereas the Tie1 gene is more commonly present. However, Tie1-driven signaling pathways, including ligands and cellular functions, are not well understood. Here, we performed comprehensive mutant analyses of angiopoietins and Tie receptors in zebrafish and found that only angpt1 and tie1 mutants show defects in trunk lymphatic vessel development. Among zebrafish angiopoietins, only Angpt1 binds to Tie1 as a ligand. We indirectly monitored Ang1/Tie1 signaling and detected Tie1 activation in sprouting endothelial cells, where Tie1 inhibits nuclear import of EGFP-Foxo1a. Angpt1/Tie1 signaling functions in endothelial cell migration and proliferation, and in lymphatic specification during early lymphangiogenesis, at least in part by modulating Vegfc/Vegfr3 signaling. Thus, we show that Angpt1/Tie1 signaling constitutes an essential signaling pathway for lymphatic development in zebrafish.
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Affiliation(s)
- Nanami Morooka
- Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 564-8565, Japan
- Department of Medical Physiology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Ning Gui
- Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 564-8565, Japan
| | - Koji Ando
- Department of Cardiac Regeneration Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 564-8565, Japan
| | - Keisuke Sako
- Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 564-8565, Japan
| | - Moe Fukumoto
- Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 564-8565, Japan
| | - Urara Hasegawa
- Department of Materials Science and Engineering, The Pennsylvania State University, Steidle Building, University Park, Pennsylvania 16802, United States
| | - Melina Hußmann
- Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, 48149 Münster, Germany
| | - Stefan Schulte-Merker
- Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, 48149 Münster, Germany
| | - Naoki Mochizuki
- Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 564-8565, Japan
| | - Hiroyuki Nakajima
- Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 564-8565, Japan
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Bowman C, Rockson SG. Genetic causes of lymphatic disorders: recent updates on the clinical and molecular aspects of lymphatic disease. Curr Opin Cardiol 2024; 39:170-177. [PMID: 38483006 DOI: 10.1097/hco.0000000000001116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
PURPOSE OF REVIEW The lymphatic system facilitates several key functions that limit significant morbidity and mortality. Despite the impact and burden of lymphatic disorders, there are many remaining disorders whose genetic substrate remains unknown. The purpose of this review is to provide an update on the genetic causes of lymphatic disorders, while reporting on newly proposed clinical classifications of lymphatic disease. RECENT FINDINGS We reviewed several new mutations in genes that have been identified as potential causes of lymphatic disorders including: MDFIC, EPHB 4 , and ANGPT2. Furthermore, the traditional St. George's Classification system for primary lymphatic anomalies has been updated to reflect the use of genetic testing, both as a tool for the clinical identification of lymphatic disease and as a method through which new sub-classifications of lymphatic disorders have been established within this framework. Finally, we highlighted recent clinical studies that have explored the impact of therapies such as sirolimus, ketoprofen, and acebilustat on lymphatic disorders. SUMMARY Despite a growing body of evidence, current literature demonstrates a persistent gap in the number of known genes responsible for lymphatic disease entities. Recent clinical classification tools have been introduced in order to integrate traditional symptom- and time-based diagnostic approaches with modern genetic classifications, as highlighted in the updated St. George's classification system. With the introduction of this novel approach, clinicians may be better equipped to recognize established disease and, potentially, to identify novel causal mutations. Further research is needed to identify additional genetic causes of disease and to optimize current clinical tools for diagnosis and treatment.
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Affiliation(s)
- Catharine Bowman
- Stanford University School of Medicine, Stanford, California, USA
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Bowman C, Rockson SG. The Role of Inflammation in Lymphedema: A Narrative Review of Pathogenesis and Opportunities for Therapeutic Intervention. Int J Mol Sci 2024; 25:3907. [PMID: 38612716 PMCID: PMC11011271 DOI: 10.3390/ijms25073907] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 03/20/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Lymphedema is a chronic and progressive disease of the lymphatic system characterized by inflammation, increased adipose deposition, and tissue fibrosis. Despite early hypotheses identifying lymphedema as a disease of mechanical lymphatic disruption alone, the progressive inflammatory nature underlying this condition is now well-established. In this review, we provide an overview of the various inflammatory mechanisms that characterize lymphedema development and progression. These mechanisms contribute to the acute and chronic phases of lymphedema, which manifest clinically as inflammation, fibrosis, and adiposity. Furthermore, we highlight the interplay between current therapeutic modalities and the underlying inflammatory microenvironment, as well as opportunities for future therapeutic development.
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Affiliation(s)
- Catharine Bowman
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA;
- Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Stanley G. Rockson
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA;
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7
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Zhou YW, Ren Y, Lu MM, Xu LL, Cheng WX, Zhang MM, Ding LP, Chen D, Gao JG, Du J, Jin CL, Chen CX, Li YF, Cheng T, Jiang PL, Yang YD, Qian PX, Xu PF, Jin X. Crohn's disease as the intestinal manifestation of pan-lymphatic dysfunction: An exploratory proposal based on basic and clinical data. World J Gastroenterol 2024; 30:34-49. [PMID: 38293325 PMCID: PMC10823898 DOI: 10.3748/wjg.v30.i1.34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/08/2023] [Accepted: 12/27/2023] [Indexed: 01/06/2024] Open
Abstract
Crohn's disease (CD) is caused by immune, environmental, and genetic factors. It can involve the entire gastrointestinal tract, and although its prevalence is rapidly increasing its etiology remains unclear. Emerging biological and small-molecule drugs have advanced the treatment of CD; however, a considerable proportion of patients are non-responsive to all known drugs. To achieve a breakthrough in this field, innovations that could guide the further development of effective therapies are of utmost urgency. In this review, we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases, and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data. The supporting evidence is fully summarized, including the existence of lymphatic system dysfunction, recognition of the inside-out model, disorders of immune cells, changes in cell plasticity, partial overlap of the underlying mechanisms, and common gut-derived fatty and bile acid metabolism. Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases, especially CD, as this model is good at presenting and mimicking lymphatic dysfunction. More importantly, the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.
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Affiliation(s)
- Yu-Wei Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Yue Ren
- Department of Gastroenterology, The Second Hospital of Jiaxing, Jiaxing 314000, Zhejiang Province, China
| | - Miao-Miao Lu
- Endoscopy Center, Children’s Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Ling-Ling Xu
- Department of Gastroenterology, The Second People’s Hospital of Yuhang District, Hangzhou 310000, Zhejiang Province, China
| | - Wei-Xin Cheng
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Meng-Meng Zhang
- Department of Gastroenterology, Hangzhou Shangcheng District People’s Hospital, Hangzhou 310003, Zhejiang Province, China
| | - Lin-Ping Ding
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Dong Chen
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Jian-Guo Gao
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Juan Du
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Ci-Liang Jin
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Chun-Xiao Chen
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Yun-Fei Li
- Women’s Hospital and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Tao Cheng
- Women’s Hospital and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Peng-Lei Jiang
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Yi-Da Yang
- Department of Infectious Disease, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Peng-Xu Qian
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Peng-Fei Xu
- Women’s Hospital and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Xi Jin
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
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Lee E, O’Keefe S, Leong A, Park HR, Varadarajan J, Chowdhury S, Hiner S, Kim S, Shiva A, Friedman RA, Remotti H, Fojo T, Yang HW, Thurston G, Kim M. Angiopoietin-2 blockade suppresses growth of liver metastases from pancreatic neuroendocrine tumors by promoting T cell recruitment. J Clin Invest 2023; 133:e167994. [PMID: 37843277 PMCID: PMC10575726 DOI: 10.1172/jci167994] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 08/15/2023] [Indexed: 10/17/2023] Open
Abstract
Improving the management of metastasis in pancreatic neuroendocrine tumors (PanNETs) is critical, as nearly half of patients with PanNETs present with liver metastases, and this accounts for the majority of patient mortality. We identified angiopoietin-2 (ANGPT2) as one of the most upregulated angiogenic factors in RNA-Seq data from human PanNET liver metastases and found that higher ANGPT2 expression correlated with poor survival rates. Immunohistochemical staining revealed that ANGPT2 was localized to the endothelial cells of blood vessels in PanNET liver metastases. We observed an association between the upregulation of endothelial ANGPT2 and liver metastatic progression in both patients and transgenic mouse models of PanNETs. In human and mouse PanNET liver metastases, ANGPT2 upregulation coincided with poor T cell infiltration, indicative of an immunosuppressive tumor microenvironment. Notably, both pharmacologic inhibition and genetic deletion of ANGPT2 in PanNET mouse models slowed the growth of PanNET liver metastases. Furthermore, pharmacologic inhibition of ANGPT2 promoted T cell infiltration and activation in liver metastases, improving the survival of mice with metastatic PanNETs. These changes were accompanied by reduced plasma leakage and improved vascular integrity in metastases. Together, these findings suggest that ANGPT2 blockade may be an effective strategy for promoting T cell infiltration and immunostimulatory reprogramming to reduce the growth of liver metastases in PanNETs.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Tito Fojo
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | | | - Gavin Thurston
- Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA
| | - Minah Kim
- Department of Pathology and Cell Biology
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9
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Sato-Nishiuchi R, Doiguchi M, Morooka N, Sekiguchi K. Polydom/SVEP1 binds to Tie1 and promotes migration of lymphatic endothelial cells. J Cell Biol 2023; 222:e202208047. [PMID: 37338522 PMCID: PMC10281526 DOI: 10.1083/jcb.202208047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 04/13/2023] [Accepted: 06/05/2023] [Indexed: 06/21/2023] Open
Abstract
Polydom is an extracellular matrix protein involved in lymphatic vessel development. Polydom-deficient mice die immediately after birth due to defects in lymphatic vessel remodeling, but the mechanism involved is poorly understood. Here, we report that Polydom directly binds to Tie1, an orphan receptor in the Angiopoietin-Tie axis, and facilitates migration of lymphatic endothelial cells (LECs) in a Tie1-dependent manner. Polydom-induced LEC migration is diminished by PI3K inhibitors but not by an ERK inhibitor, suggesting that the PI3K/Akt signaling pathway is involved in Polydom-induced LEC migration. In line with this possibility, Akt phosphorylation in LECs is enhanced by Polydom although no significant Tie1 phosphorylation is induced by Polydom. LECs also exhibited nuclear exclusion of Foxo1, a signaling event downstream of Akt activation, which was impaired in Polydom-deficient mice. These findings indicate that Polydom is a physiological ligand for Tie1 and participates in lymphatic vessel development through activation of the PI3K/Akt pathway.
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Affiliation(s)
- Ryoko Sato-Nishiuchi
- Division of Matrixome Research and Application, Institute for Protein Research, Osaka University , Suita, Japan
| | - Masamichi Doiguchi
- Division of Matrixome Research and Application, Institute for Protein Research, Osaka University , Suita, Japan
| | - Nanami Morooka
- Division of Matrixome Research and Application, Institute for Protein Research, Osaka University , Suita, Japan
- Department of Medical Physiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kiyotoshi Sekiguchi
- Division of Matrixome Research and Application, Institute for Protein Research, Osaka University , Suita, Japan
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10
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Park HR, Shiva A, Cummings P, Kim S, Kim S, Lee E, Leong A, Chowdhury S, Shawber C, Carvajal R, Thurston G, An JY, Lund AW, Yang HW, Kim M. Angiopoietin-2-Dependent Spatial Vascular Destabilization Promotes T-cell Exclusion and Limits Immunotherapy in Melanoma. Cancer Res 2023; 83:1968-1983. [PMID: 37093870 PMCID: PMC10267677 DOI: 10.1158/0008-5472.can-22-2838] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 01/13/2023] [Accepted: 04/18/2023] [Indexed: 04/25/2023]
Abstract
T-cell position in the tumor microenvironment determines the probability of target encounter and tumor killing. CD8+ T-cell exclusion from the tumor parenchyma is associated with poor response to immunotherapy, and yet the biology that underpins this distinct pattern remains unclear. Here we show that the vascular destabilizing factor angiopoietin-2 (ANGPT2) causes compromised vascular integrity in the tumor periphery, leading to impaired T-cell infiltration to the tumor core. The spatial regulation of ANGPT2 in whole tumor cross-sections was analyzed in conjunction with T-cell distribution, vascular integrity, and response to immunotherapy in syngeneic murine melanoma models. T-cell exclusion was associated with ANGPT2 upregulation and elevated vascular leakage at the periphery of human and murine melanomas. Both pharmacologic and genetic blockade of ANGPT2 promoted CD8+ T-cell infiltration into the tumor core, exerting antitumor effects. Importantly, the reversal of T-cell exclusion following ANGPT2 blockade not only enhanced response to anti-PD-1 immune checkpoint blockade therapy in immunogenic, therapy-responsive mouse melanomas, but it also rendered nonresponsive tumors susceptible to immunotherapy. Therapeutic response after ANGPT2 blockade, driven by improved CD8+ T-cell infiltration to the tumor core, coincided with spatial TIE2 signaling activation and increased vascular integrity at the tumor periphery where endothelial expression of adhesion molecules was reduced. These data highlight ANGPT2/TIE2 signaling as a key mediator of T-cell exclusion and a promising target to potentiate immune checkpoint blockade efficacy in melanoma. SIGNIFICANCE ANGPT2 limits the efficacy of immunotherapy by inducing vascular destabilization at the tumor periphery to promote T-cell exclusion.
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Affiliation(s)
- Ha-Ram Park
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Anahita Shiva
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Portia Cummings
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Seoyeon Kim
- School of Biosystems and Biomedical Sciences, College of Health Science, Korea University, Seoul, Korea
| | - Sungsoo Kim
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Eunhyeong Lee
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Alessandra Leong
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Subrata Chowdhury
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Carrie Shawber
- Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, New York
| | - Richard Carvajal
- Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | | | - Joon-Yong An
- School of Biosystems and Biomedical Sciences, College of Health Science, Korea University, Seoul, Korea
| | - Amanda W. Lund
- Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, NYU Langone Health, New York, New York
| | - Hee Won Yang
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Minah Kim
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
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11
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Korhonen EA, Murtomäki A, Jha SK, Anisimov A, Pink A, Zhang Y, Stritt S, Liaqat I, Stanczuk L, Alderfer L, Sun Z, Kapiainen E, Singh A, Sultan I, Lantta A, Leppänen VM, Eklund L, He Y, Augustin HG, Vaahtomeri K, Saharinen P, Mäkinen T, Alitalo K. Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell surface expression. J Clin Invest 2022; 132:155478. [PMID: 35763346 PMCID: PMC9337826 DOI: 10.1172/jci155478] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 06/16/2022] [Indexed: 11/17/2022] Open
Abstract
Vascular endothelial growth factor C (VEGF-C) induces lymphangiogenesis via VEGF receptor 3 (VEGFR3), which is encoded by the most frequently mutated gene in human primary lymphedema. Angiopoietins (Angs) and their Tie receptors regulate lymphatic vessel development, and mutations of the ANGPT2 gene were recently found in human primary lymphedema. However, the mechanistic basis of Ang2 activity in lymphangiogenesis is not fully understood. Here, we used gene deletion, blocking Abs, transgene induction, and gene transfer to study how Ang2, its Tie2 receptor, and Tie1 regulate lymphatic vessels. We discovered that VEGF-C–induced Ang2 secretion from lymphatic endothelial cells (LECs) was involved in full Akt activation downstream of phosphoinositide 3 kinase (PI3K). Neonatal deletion of genes encoding the Tie receptors or Ang2 in LECs, or administration of an Ang2-blocking Ab decreased VEGFR3 presentation on LECs and inhibited lymphangiogenesis. A similar effect was observed in LECs upon deletion of the PI3K catalytic p110α subunit or with small-molecule inhibition of a constitutively active PI3K located downstream of Ang2. Deletion of Tie receptors or blockade of Ang2 decreased VEGF-C–induced lymphangiogenesis also in adult mice. Our results reveal an important crosstalk between the VEGF-C and Ang signaling pathways and suggest new avenues for therapeutic manipulation of lymphangiogenesis by targeting Ang2/Tie/PI3K signaling.
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Affiliation(s)
- Emilia A Korhonen
- Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland
| | - Aino Murtomäki
- Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland
| | - Sawan Kumar Jha
- Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland
| | - Andrey Anisimov
- Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland
| | - Anne Pink
- Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland
| | - Yan Zhang
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Simon Stritt
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Inam Liaqat
- Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland
| | - Lukas Stanczuk
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Laura Alderfer
- Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland
| | - Zhiliang Sun
- Cyrus Tang Hematology Center, Soochow University, Suzhou, China
| | - Emmi Kapiainen
- Oulu Centre for Cell-Matrix Research, Faculty of Biochemistry and Molecular, University of Oulu, Oulu, Finland
| | - Abhishek Singh
- Oulu Centre for Cell-Matrix Research, Faculty of Biochemistry and Molecular, University of Oulu, Oulu, Finland
| | - Ibrahim Sultan
- Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland
| | - Anni Lantta
- Translational Cancer Medicine Program, University of Helsinki, Helsinki, Finland
| | - Veli-Matti Leppänen
- Translational Cancer Medicine Program, University of Helsinki, Helsinki, Finland
| | - Lauri Eklund
- Oulu Centre for Cell-Matrix Research, Faculty of Biochemistry and Molecular, University of Oulu, Oulu, Finland
| | - Yulong He
- Cyrus Tang Hematology Center, Soochow University, Suzhou, China
| | - Hellmut G Augustin
- Division of Vascular Oncology and Metastasis, German Cancer Research Center, Heidelberg, Germany
| | - Kari Vaahtomeri
- Translational Cancer Medicine Program, University of Helsinki, Helsinki, Finland
| | - Pipsa Saharinen
- Translational Cancer Medicine Program, University of Helsinki, Helsinki, Finland
| | - Taija Mäkinen
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Kari Alitalo
- Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland
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12
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Aqueous outflow channels and its lymphatic association: A review. Surv Ophthalmol 2021; 67:659-674. [PMID: 34656556 PMCID: PMC9008077 DOI: 10.1016/j.survophthal.2021.10.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 10/07/2021] [Accepted: 10/11/2021] [Indexed: 11/24/2022]
Abstract
The human eye has a unique immune architecture and behavior. While the conjunctiva is known to have a well-defined lymphatic drainage system, the cornea, sclera, and uveal tissues were historically considered "alymphatic" and thought to be immune privileged. The very fact that the aqueous outflow channels carry a clear fluid (aqueous humor) along the outflow pathway makes it hard to ignore its lymphatic-like characteristics. The development of novel lymphatic lineage markers and expression of these markers in aqueous outflow channels and improved imaging capabilities has sparked a renewed interest in the study of ocular lymphatics. Ophthalmic lymphatic research has had a directional shift over the last decade, offering an exciting new physiological platform that needs further in-depth understanding. The evidence of a presence of distinct lymphatic channels in the human ciliary body is gaining significant traction. The uveolymphatic pathway is an alternative new route for aqueous outflow and adds a new dimension to pathophysiology and management of glaucoma. Developing novel animal models, markers, and non-invasive imaging tools to delineate the core anatomical structure and physiological functions may help pave some crucial pathways to understand disease pathophysiology and help develop novel targeted therapeutic approaches for glaucoma.
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13
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Ducoli L, Detmar M. Beyond PROX1: transcriptional, epigenetic, and noncoding RNA regulation of lymphatic identity and function. Dev Cell 2021; 56:406-426. [PMID: 33621491 DOI: 10.1016/j.devcel.2021.01.018] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 12/08/2020] [Accepted: 01/25/2021] [Indexed: 12/11/2022]
Abstract
The lymphatic vascular system acts as the major transportation highway of tissue fluids, and its activation or impairment is associated with a wide range of diseases. There has been increasing interest in understanding the mechanisms that control lymphatic vessel formation (lymphangiogenesis) and function in development and disease. Here, we discuss recent insights into new players whose identification has contributed to deciphering the lymphatic regulatory code. We reveal how lymphatic endothelial cells, the building blocks of lymphatic vessels, utilize their transcriptional, post-transcriptional, and epigenetic portfolio to commit to and maintain their vascular lineage identity and function, with a particular focus on development.
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Affiliation(s)
- Luca Ducoli
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland; Molecular Life Sciences PhD Program, Swiss Federal Institute of Technology and University of Zürich, Zurich, Switzerland
| | - Michael Detmar
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland.
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14
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Leppänen VM, Brouillard P, Korhonen EA, Sipilä T, Jha SK, Revencu N, Labarque V, Fastré E, Schlögel M, Ravoet M, Singer A, Luzzatto C, Angelone D, Crichiutti G, D'Elia A, Kuurne J, Elamaa H, Koh GY, Saharinen P, Vikkula M, Alitalo K. Characterization of ANGPT2 mutations associated with primary lymphedema. Sci Transl Med 2021; 12:12/560/eaax8013. [PMID: 32908006 DOI: 10.1126/scitranslmed.aax8013] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 12/31/2019] [Accepted: 08/14/2020] [Indexed: 12/11/2022]
Abstract
Primary lymphedema is caused by developmental and functional defects of the lymphatic vascular system that result in accumulation of protein-rich fluid in tissues, resulting in edema. The 28 currently known genes causing primary lymphedema can explain <30% of cases. Angiopoietin 1 (ANGPT1) and ANGPT2 function via the TIE1-TIE2 (tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 and 2) receptor complex and α5β1 integrin to form an endothelial cell signaling pathway that is critical for blood and lymphatic vessel formation and remodeling during embryonic development, as well as for homeostasis of the mature vasculature. By screening a cohort of 543 individuals affected by primary lymphedema, we identified one heterozygous de novo ANGPT2 whole-gene deletion and four heterozygous ANGPT2 missense mutations. Functional analyses revealed three missense mutations that resulted in decreased ANGPT2 secretion and inhibited the secretion of wild-type (WT)-ANGPT2, suggesting that they have a dominant-negative effect on ANGPT2 signaling. WT-ANGPT2 and soluble mutants T299M and N304K activated TIE1 and TIE2 in an autocrine assay in human lymphatic endothelial cells. Molecular modeling and biophysical studies showed that amino-terminally truncated ANGPT subunits formed asymmetrical homodimers that bound TIE2 in a 2:1 ratio. The T299M mutant, located in the dimerization interphase, showed reduced integrin α5 binding, and its expression in mouse skin promoted hyperplasia and dilation of cutaneous lymphatic vessels. These results demonstrate that primary lymphedema can be associated with ANGPT2 mutations and provide insights into TIE1 and TIE2 activation mechanisms.
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Affiliation(s)
- Veli-Matti Leppänen
- Wihuri Research Institute, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland. .,Translational Cancer Medicine Program, Faculty of Medicine and Helsinki Institute of Life Science, 00014 University of Helsinki, Finland
| | - Pascal Brouillard
- Human Molecular Genetics, de Duve Institute, University of Louvain, 1200 Brussels, Belgium.
| | - Emilia A Korhonen
- Wihuri Research Institute, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland
| | - Tuomas Sipilä
- Wihuri Research Institute, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland
| | - Sawan Kumar Jha
- Translational Cancer Medicine Program, Faculty of Medicine and Helsinki Institute of Life Science, 00014 University of Helsinki, Finland
| | - Nicole Revencu
- Center for Human Genetics, Cliniques universitaires Saint-Luc, University of Louvain, 1200 Brussels, Belgium
| | - Veerle Labarque
- Centre for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium
| | - Elodie Fastré
- Human Molecular Genetics, de Duve Institute, University of Louvain, 1200 Brussels, Belgium
| | - Matthieu Schlögel
- Human Molecular Genetics, de Duve Institute, University of Louvain, 1200 Brussels, Belgium
| | - Marie Ravoet
- Center for Human Genetics, Cliniques universitaires Saint-Luc, University of Louvain, 1200 Brussels, Belgium
| | | | | | | | - Giovanni Crichiutti
- Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, 33100 Udine, Italy
| | - Angela D'Elia
- Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, 33100 Udine, Italy
| | - Jaakko Kuurne
- Wihuri Research Institute, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland
| | - Harri Elamaa
- Oulu Centre for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90220 Oulu, Finland
| | - Gou Young Koh
- Center for Vascular Research, Institute of Basic Science (IBS), 34141 Daejeon, Republic of Korea.,Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), 34141 Daejeon, Republic of Korea
| | - Pipsa Saharinen
- Wihuri Research Institute, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland.,Translational Cancer Medicine Program, Faculty of Medicine and Helsinki Institute of Life Science, 00014 University of Helsinki, Finland
| | - Miikka Vikkula
- Human Molecular Genetics, de Duve Institute, University of Louvain, 1200 Brussels, Belgium. .,Walloon Excellence in Lifesciences and Biotechnology (WELBIO), University of Louvain, 1200 Brussels, Belgium
| | - Kari Alitalo
- Wihuri Research Institute, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland. .,Translational Cancer Medicine Program, Faculty of Medicine and Helsinki Institute of Life Science, 00014 University of Helsinki, Finland
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15
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Guo Z, Mo Z. Regulation of endothelial cell differentiation in embryonic vascular development and its therapeutic potential in cardiovascular diseases. Life Sci 2021; 276:119406. [PMID: 33785330 DOI: 10.1016/j.lfs.2021.119406] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 03/05/2021] [Accepted: 03/14/2021] [Indexed: 12/17/2022]
Abstract
During vertebrate development, the cardiovascular system begins operating earlier than any other organ in the embryo. Endothelial cell (EC) forms the inner lining of blood vessels, and its extensive proliferation and migration are requisite for vasculogenesis and angiogenesis. Many aspects of cellular biology are involved in vasculogenesis and angiogenesis, including the tip versus stalk cell specification. Recently, epigenetics has attracted growing attention in regulating embryonic vascular development and controlling EC differentiation. Some proteins that regulate chromatin structure have been shown to be directly implicated in human cardiovascular diseases. Additionally, the roles of important EC signaling such as vascular endothelial growth factor and its receptors, angiopoietin-1 and tyrosine kinase containing immunoglobulin and epidermal growth factor homology domain-2, and transforming growth factor-β in EC differentiation during embryonic vasculature development are briefly discussed in this review. Recently, the transplantation of human induced pluripotent stem cell (iPSC)-ECs are promising approaches for the treatment of ischemic cardiovascular disease including myocardial infarction. Patient-specific iPSC-derived EC is a potential new target to study differences in gene expression or response to drugs. However, clinical application of the iPSC-ECs in regenerative medicine is often limited by the challenges of maintaining cell viability and function. Therefore, novel insights into the molecular mechanisms underlying EC differentiation might provide a better understanding of embryonic vascular development and bring out more effective EC-based therapeutic strategies for cardiovascular diseases.
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Affiliation(s)
- Zi Guo
- Department of Endocrinology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhaohui Mo
- Department of Endocrinology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
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16
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González-Loyola A, Petrova TV. Development and aging of the lymphatic vascular system. Adv Drug Deliv Rev 2021; 169:63-78. [PMID: 33316347 DOI: 10.1016/j.addr.2020.12.005] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/22/2020] [Accepted: 12/07/2020] [Indexed: 12/13/2022]
Abstract
The lymphatic vasculature has a pivotal role in regulating body fluid homeostasis, immune surveillance and dietary fat absorption. The increasing number of in vitro and in vivo studies in the last decades has shed light on the processes of lymphatic vascular development and function. Here, we will discuss the current progress in lymphatic vascular biology such as the mechanisms of lymphangiogenesis, lymphatic vascular maturation and maintenance and the emerging mechanisms of lymphatic vascular aging.
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Affiliation(s)
- Alejandra González-Loyola
- Department of Oncology, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Switzerland.
| | - Tatiana V Petrova
- Department of Oncology, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Switzerland.
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17
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Norden PR, Kume T. Molecular Mechanisms Controlling Lymphatic Endothelial Junction Integrity. Front Cell Dev Biol 2021; 8:627647. [PMID: 33521001 PMCID: PMC7841202 DOI: 10.3389/fcell.2020.627647] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022] Open
Abstract
The lymphatic system is essential for lipid absorption/transport from the digestive system, maintenance of tissue fluid and protein homeostasis, and immune surveillance. Despite recent progress toward understanding the cellular and molecular mechanisms underlying the formation of the lymphatic vascular system, the nature of lymphatic vessel abnormalities and disease in humans is complex and poorly understood. The mature lymphatic vasculature forms a hierarchical network in which lymphatic endothelial cells (LECs) are joined by functionally specialized cell-cell junctions to maintain the integrity of lymphatic vessels. Blind-ended and highly permeable lymphatic capillaries drain interstitial fluid via discontinuous, button-like LEC junctions, whereas collecting lymphatic vessels, surrounded by intact basement membranes and lymphatic smooth muscle cells, have continuous, zipper-like LEC junctions to transport lymph to the blood circulatory system without leakage. In this review, we discuss the recent advances in our understanding of the mechanisms by which lymphatic button- and zipper-like junctions play critical roles in lymphatic permeability and function in a tissue- and organ-specific manner, including lacteals of the small intestine. We also provide current knowledge related to key pathways and factors such as VEGF and RhoA/ROCK signaling that control lymphatic endothelial cell junctional integrity.
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Affiliation(s)
- Pieter R Norden
- Department of Medicine, Feinberg School of Medicine, Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Chicago, IL, United States
| | - Tsutomu Kume
- Department of Medicine, Feinberg School of Medicine, Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Chicago, IL, United States
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18
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Carlantoni C, Allanki S, Kontarakis Z, Rossi A, Piesker J, Günther S, Stainier DY. Tie1 regulates zebrafish cardiac morphogenesis through Tolloid-like 1 expression. Dev Biol 2021; 469:54-67. [DOI: 10.1016/j.ydbio.2020.09.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 09/10/2020] [Accepted: 09/13/2020] [Indexed: 01/13/2023]
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19
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Abstract
The lymphatic vasculature is a vital component of the vertebrate vascular system that mediates tissue fluid homeostasis, lipid uptake and immune surveillance. The development of the lymphatic vasculature starts in the early vertebrate embryo, when a subset of blood vascular endothelial cells of the cardinal veins acquires lymphatic endothelial cell fate. These cells sprout from the veins, migrate, proliferate and organize to give rise to a highly structured and unique vascular network. Cellular cross-talk, cell-cell communication and the interpretation of signals from surrounding tissues are all essential for coordinating these processes. In this chapter, we highlight new findings and review research progress with a particular focus on LEC migration and guidance, expansion of the LEC lineage, network remodeling and morphogenesis of the lymphatic vasculature.
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20
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Gengenbacher N, Singhal M, Mogler C, Hai L, Milde L, Pari AAA, Besemfelder E, Fricke C, Baumann D, Gehrs S, Utikal J, Felcht M, Hu J, Schlesner M, Offringa R, Chintharlapalli SR, Augustin HG. Timed Ang2-Targeted Therapy Identifies the Angiopoietin-Tie Pathway as Key Regulator of Fatal Lymphogenous Metastasis. Cancer Discov 2020; 11:424-445. [PMID: 33106316 DOI: 10.1158/2159-8290.cd-20-0122] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 08/13/2020] [Accepted: 10/09/2020] [Indexed: 11/16/2022]
Abstract
Recent clinical and preclinical advances have highlighted the existence of a previously hypothesized lymphogenous route of metastasis. However, due to a lack of suitable preclinical modeling tools, its contribution to long-term disease outcome and relevance for therapy remain controversial. Here, we established a genetically engineered mouse model (GEMM) fragment-based tumor model uniquely sustaining a functional network of intratumoral lymphatics that facilitates seeding of fatal peripheral metastases. Multiregimen survival studies and correlative patient data identified primary tumor-derived Angiopoietin-2 (Ang2) as a potent therapeutic target to restrict lymphogenous tumor cell dissemination. Mechanistically, tumor-associated lymphatic endothelial cells (EC), in contrast to blood vascular EC, were found to be critically addicted to the Angiopoietin-Tie pathway. Genetic manipulation experiments in combination with single-cell mapping revealed agonistically acting Ang2-Tie2 signaling as key regulator of lymphatic maintenance. Correspondingly, acute presurgical Ang2 neutralization was sufficient to prolong survival by regressing established intratumoral lymphatics, hence identifying a therapeutic regimen that warrants further clinical evaluation. SIGNIFICANCE: Exploiting multiple mouse tumor models including a unique GEMM-derived allograft system in combination with preclinical therapy designs closely matching the human situation, this study provides fundamental insight into the biology of tumor-associated lymphatic EC and defines an innovative presurgical therapeutic window of migrastatic Ang2 neutralization to restrict lymphogenous metastasis.This article is highlighted in the In This Issue feature, p. 211.
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Affiliation(s)
- Nicolas Gengenbacher
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.,Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Faculty of Biosciences, Heidelberg University, Mannheim, Germany
| | - Mahak Singhal
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.,Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Faculty of Biosciences, Heidelberg University, Mannheim, Germany
| | - Carolin Mogler
- Institute of Pathology, TUM School of Medicine, Munich, Germany
| | - Ling Hai
- Junior Group Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Laura Milde
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.,Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Faculty of Biosciences, Heidelberg University, Mannheim, Germany
| | - Ashik Ahmed Abdul Pari
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.,Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Faculty of Biosciences, Heidelberg University, Mannheim, Germany
| | - Eva Besemfelder
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Claudine Fricke
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Daniel Baumann
- Faculty of Biosciences, Heidelberg University, Mannheim, Germany.,Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stephanie Gehrs
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.,Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Faculty of Biosciences, Heidelberg University, Mannheim, Germany
| | - Jochen Utikal
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany
| | - Moritz Felcht
- Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany
| | - Junhao Hu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
| | - Matthias Schlesner
- Junior Group Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Rienk Offringa
- Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Hellmut G Augustin
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany. .,Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,German Cancer Consortium, Heidelberg, Germany
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21
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TIE1 as a Candidate Gene for Lymphatic Malformations with or without Lymphedema. Int J Mol Sci 2020; 21:ijms21186780. [PMID: 32947856 PMCID: PMC7555018 DOI: 10.3390/ijms21186780] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 09/08/2020] [Accepted: 09/08/2020] [Indexed: 12/28/2022] Open
Abstract
TIE1 is a cell surface protein expressed in endothelial cells. Involved in angiogenesis and lymphangiogenesis, including morphogenesis of lymphatic valves, TIE1 is important for lymphatic system functional integrity. The main purpose of this study was to identify different variants in the TIE1 gene that could be associated with lymphatic malformations or dysfunction and predisposition for lymphedema. In a cohort of 235 Italian lymphedema patients, who tested negative for variants in known lymphedema genes, we performed a further test for new candidate genes, including TIE1. Three probands carried different variants in TIE1. Two of these segregated with lymphedema or lymphatic dysfunction in familial cases. Variants in TIE1 could contribute to the onset of lymphedema. On the basis of our findings, we propose TIE1 as a candidate gene for comprehensive genetic testing of lymphedema.
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22
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Angiopoietin-2-integrin α5β1 signaling enhances vascular fatty acid transport and prevents ectopic lipid-induced insulin resistance. Nat Commun 2020; 11:2980. [PMID: 32532986 PMCID: PMC7293240 DOI: 10.1038/s41467-020-16795-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 05/22/2020] [Indexed: 02/07/2023] Open
Abstract
Proper storage of excessive dietary fat into subcutaneous adipose tissue (SAT) prevents ectopic lipid deposition-induced insulin resistance, yet the underlying mechanism remains unclear. Here, we identify angiopoietin-2 (Angpt2)–integrin α5β1 signaling as an inducer of fat uptake specifically in SAT. Adipocyte-specific deletion of Angpt2 markedly reduced fatty acid uptake and storage in SAT, leading to ectopic lipid accumulation in glucose-consuming organs including skeletal muscle and liver and to systemic insulin resistance. Mechanistically, Angpt2 activated integrin α5β1 signaling in the endothelium and triggered fatty acid transport via CD36 and FATP3 into SAT. Genetic or pharmacological inhibition of the endothelial integrin α5β1 recapitulated adipocyte-specific Angpt2 knockout phenotypes. Our findings demonstrate the critical roles of Angpt2–integrin α5β1 signaling in SAT endothelium in regulating whole-body fat distribution for metabolic health and highlight adipocyte–endothelial crosstalk as a potential target for prevention of ectopic lipid deposition-induced lipotoxicity and insulin resistance. Fat uptake and storage in subcutaneous adipose tissue (SAT) prevents ectopic fat accumulation and associated metabolic complications, however, the underlying mechanisms are incompletely understood. Here, the authors show that adipose angiopoietin-2 (Angpt2) enhances SAT size via increased endothelial fatty acid transport.
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23
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Pawlak JB, Caron KM. Lymphatic Programing and Specialization in Hybrid Vessels. Front Physiol 2020; 11:114. [PMID: 32153423 PMCID: PMC7044189 DOI: 10.3389/fphys.2020.00114] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 01/31/2020] [Indexed: 12/14/2022] Open
Abstract
Building on a large body of existing blood vascular research, advances in lymphatic research have helped kindle broader investigations into vascular diversity and endothelial plasticity. While the endothelium of blood and lymphatic vessels can be distinguished by a variety of molecular markers, the endothelia of uniquely diverse vascular beds can possess distinctly heterogeneous or hybrid expression patterns. These expression patterns can then provide further insight on the development of these vessels and how they perform their specialized function. In this review we examine five highly specialized hybrid vessel beds that adopt partial lymphatic programing for their specialized vascular functions: the high endothelial venules of secondary lymphoid organs, the liver sinusoid, the Schlemm’s canal of the eye, the renal ascending vasa recta, and the remodeled placental spiral artery. We summarize the morphology and endothelial expression pattern of these vessels, compare them to each other, and interrogate their specialized functions within the broader blood and lymphatic vascular systems.
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Affiliation(s)
- John B Pawlak
- Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Kathleen M Caron
- Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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Zhang B, Yin X, Li J, Ren C, Liu W, Liu G, Lu P. Essential contribution of macrophage Tie2 signal mediated autophagy in laser-induced choroidal neovascularization. Exp Eye Res 2020; 193:107972. [PMID: 32059975 DOI: 10.1016/j.exer.2020.107972] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 01/10/2020] [Accepted: 02/11/2020] [Indexed: 12/25/2022]
Abstract
Autophagy plays critical roles in various ocular diseases, including age-related macular degeneration (AMD). Tie2-expressing macrophages (TEMs) play crucial roles in angiogenesis. To investigate the role of TEMs and autophagy in the development of AMD, we employed macrophage-specific Tie2 knockout mice and used a laser-induced choroidal neovascularization (CNV). The results showed that TEMs can promote CNV formation by up-regulating the level of autophagy. These results were further verified by in vitro cell experiments that peritoneal macrophages from Tie2 knockout mice can inhibit the expression of autophagy-related factors and inhibit the expression of angiogenic factor of VEGF by activating AMPK signaling pathway. Our results suggest that TEMs and macrophage Tie2 signal mediated-autophagy play critical role in experimental CNV, and they may be novel preventive targets for AMD treatment.
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Affiliation(s)
- Bingyu Zhang
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, Jiangsu Province, PR China
| | - Xue Yin
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, Jiangsu Province, PR China
| | - Jianqing Li
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, Jiangsu Province, PR China
| | - Chi Ren
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, Jiangsu Province, PR China
| | - Weiming Liu
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, Jiangsu Province, PR China
| | - Gaoqin Liu
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, Jiangsu Province, PR China
| | - Peirong Lu
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, Jiangsu Province, PR China.
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25
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Abstract
Tumor blood vessel formation (angiogenesis) is essential for tumor growth and metastasis. Two main endothelial ligand–receptor pathways regulating angiogenesis are vascular endothelial growth factor (VEGF) receptor and angiopoietin-TIE receptor pathways. The angiopoietin-TIE pathway is required for the remodeling and maturation of the blood and lymphatic vessels during embryonic development after VEGF and VEGF-C mediated development of the primary vascular plexus. Angiopoietin-1 (ANGPT1) stabilizes the vasculature after angiogenic processes, via tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (TIE2) activation. In contrast, ANGPT2 is upregulated at sites of vascular remodeling. ANGPT2 is secreted by activated endothelial cells in inflammation, promoting vascular destabilization. ANGPT2 has been found to be expressed in many human cancers. Intriguingly, in preclinical models inhibition of ANGPT2 has provided promising results in preventing tumor angiogenesis, tumor growth, and metastasis, making it an attractive candidate to target in tumors. However, until now the first ANGPT2 targeting therapies have been less effective in clinical trials than in experimental models. Additionally, in preclinical models combined therapy against ANGPT2 and VEGF or immune checkpoint inhibitors has been superior to monotherapies, and these pathways are also targeted in early clinical trials. In order to improve current anti-angiogenic therapies and successfully exploit ANGPT2 as a target for cancer treatment, the biology of the angiopoietin-TIE pathway needs to be profoundly clarified.
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Affiliation(s)
- Dieter Marmé
- Tumor Biology Center, Freiburg, Baden-Württemberg Germany
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26
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Breslin JW, Yang Y, Scallan JP, Sweat RS, Adderley SP, Murfee WL. Lymphatic Vessel Network Structure and Physiology. Compr Physiol 2018; 9:207-299. [PMID: 30549020 PMCID: PMC6459625 DOI: 10.1002/cphy.c180015] [Citation(s) in RCA: 210] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The lymphatic system is comprised of a network of vessels interrelated with lymphoid tissue, which has the holistic function to maintain the local physiologic environment for every cell in all tissues of the body. The lymphatic system maintains extracellular fluid homeostasis favorable for optimal tissue function, removing substances that arise due to metabolism or cell death, and optimizing immunity against bacteria, viruses, parasites, and other antigens. This article provides a comprehensive review of important findings over the past century along with recent advances in the understanding of the anatomy and physiology of lymphatic vessels, including tissue/organ specificity, development, mechanisms of lymph formation and transport, lymphangiogenesis, and the roles of lymphatics in disease. © 2019 American Physiological Society. Compr Physiol 9:207-299, 2019.
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Affiliation(s)
- Jerome W. Breslin
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Ying Yang
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Joshua P. Scallan
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Richard S. Sweat
- Department of Biomedical Engineering, Tulane University, New Orleans, LA
| | - Shaquria P. Adderley
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - W. Lee Murfee
- Department of Biomedical Engineering, University of Florida, Gainesville, FL
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Lee SJ, Lee CK, Kang S, Park I, Kim YH, Kim SK, Hong SP, Bae H, He Y, Kubota Y, Koh GY. Angiopoietin-2 exacerbates cardiac hypoxia and inflammation after myocardial infarction. J Clin Invest 2018; 128:5018-5033. [PMID: 30295643 DOI: 10.1172/jci99659] [Citation(s) in RCA: 120] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 08/21/2018] [Indexed: 12/15/2022] Open
Abstract
Emerging evidence indicates that angiopoietin-2 (Angpt2), a well-recognized vascular destabilizing factor, is a biomarker of poor outcome in ischemic heart disease. However, its precise role in postischemic cardiovascular remodeling is poorly understood. Here, we show that Angpt2 plays multifaceted roles in the exacerbation of cardiac hypoxia and inflammation after myocardial ischemia. Angpt2 was highly expressed in endothelial cells at the infarct border zone after myocardial infarction (MI) or ischemia/reperfusion injury in mice. In the acute phase of MI, endothelial-derived Angpt2 antagonized Angpt1/Tie2 signaling, which was greatly involved in pericyte detachment, vascular leakage, increased adhesion molecular expression, degradation of the glycocalyx and extracellular matrix, and enhanced neutrophil infiltration and hypoxia in the infarct border area. In the chronic remodeling phase after MI, endothelial- and macrophage-derived Angpt2 continuously promoted abnormal vascular remodeling and proinflammatory macrophage polarization through integrin α5β1 signaling, worsening cardiac hypoxia and inflammation. Accordingly, inhibition of Angpt2 either by gene deletion or using an anti-Angpt2 blocking antibody substantially alleviated these pathological findings and ameliorated postischemic cardiovascular remodeling. Blockade of Angpt2 thus has potential as a therapeutic option for ischemic heart failure.
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Affiliation(s)
- Seung-Jun Lee
- Center for Vascular Research, Institute for Basic Science, Daejeon, South Korea
| | - Choong-Kun Lee
- Center for Vascular Research, Institute for Basic Science, Daejeon, South Korea.,Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
| | - Seok Kang
- Center for Vascular Research, Institute for Basic Science, Daejeon, South Korea.,Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
| | - Intae Park
- Center for Vascular Research, Institute for Basic Science, Daejeon, South Korea.,Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
| | - Yoo Hyung Kim
- Center for Vascular Research, Institute for Basic Science, Daejeon, South Korea.,Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
| | - Seo Ki Kim
- Center for Vascular Research, Institute for Basic Science, Daejeon, South Korea.,Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
| | - Seon Pyo Hong
- Center for Vascular Research, Institute for Basic Science, Daejeon, South Korea.,Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
| | - Hosung Bae
- Center for Vascular Research, Institute for Basic Science, Daejeon, South Korea.,Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
| | - Yulong He
- Cyrus Tang Hematology Center, Soochow University, Suzhou, China
| | - Yoshiaki Kubota
- The Laboratory of Vascular Biology, School of Medicine, Keio University, Tokyo, Japan
| | - Gou Young Koh
- Center for Vascular Research, Institute for Basic Science, Daejeon, South Korea.,Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
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28
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Jha SK, Rauniyar K, Jeltsch M. Key molecules in lymphatic development, function, and identification. Ann Anat 2018; 219:25-34. [PMID: 29842991 DOI: 10.1016/j.aanat.2018.05.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 05/02/2018] [Accepted: 05/03/2018] [Indexed: 12/18/2022]
Abstract
While both blood and lymphatic vessels transport fluids and thus share many similarities, they also show functional and structural differences, which can be used to differentiate them. Specific visualization of lymphatic vessels has historically been and still is a pivot point in lymphatic research. Many of the proteins that are investigated by molecular biologists in lymphatic research have been defined as marker molecules, i.e. to visualize and distinguish lymphatic endothelial cells (LECs) from other cell types, most notably from blood vascular endothelial cells (BECs) and cells of the hematopoietic lineage. Among the factors that drive the developmental differentiation of lymphatic structures from venous endothelium, Prospero homeobox protein 1 (PROX1) is the master transcriptional regulator. PROX1 maintains lymphatic identity also in the adult organism and thus is a universal LEC marker. Vascular endothelial growth factor receptor-3 (VEGFR-3) is the major tyrosine kinase receptor that drives LEC proliferation and migration. The major activator for VEGFR-3 is vascular endothelial growth factor-C (VEGF-C). However, before VEGF-C can signal, it needs to be proteolytically activated by an extracellular protein complex comprised of Collagen and calcium binding EGF domains 1 (CCBE1) protein and the protease A disintegrin and metallopeptidase with thrombospondin type 1 motif 3 (ADAMTS3). This minireview attempts to give an overview of these and a few other central proteins that scientific inquiry has linked specifically to the lymphatic vasculature. It is limited in scope to a brief description of their main functions, properties and developmental roles.
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Affiliation(s)
- Sawan Kumar Jha
- Translational Cancer Biology Research Program, University of Helsinki, Finland
| | - Khushbu Rauniyar
- Translational Cancer Biology Research Program, University of Helsinki, Finland
| | - Michael Jeltsch
- Translational Cancer Biology Research Program, University of Helsinki, Finland; Wihuri Research Institute, Biomedicum Helsinki, Finland.
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29
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Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP. Proc Natl Acad Sci U S A 2018; 115:1298-1303. [PMID: 29358379 PMCID: PMC5819405 DOI: 10.1073/pnas.1714446115] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
The angiopoietin (ANGPT)-TIE2/TEK signaling pathway is essential for blood and lymphatic vascular homeostasis. ANGPT1 is a potent TIE2 activator, whereas ANGPT2 functions as a context-dependent agonist/antagonist. In disease, ANGPT2-mediated inhibition of TIE2 in blood vessels is linked to vascular leak, inflammation, and metastasis. Using conditional knockout studies in mice, we show TIE2 is predominantly activated by ANGPT1 in the cardiovascular system and by ANGPT2 in the lymphatic vasculature. Mechanisms underlying opposing actions of ANGPT2 in blood vs. lymphatic endothelium are poorly understood. Here we show the endothelial-specific phosphatase VEPTP (vascular endothelial protein tyrosine phosphatase) determines TIE2 response to ANGPT2. VEPTP is absent from lymphatic endothelium in mouse in vivo, permitting ANGPT2/TIE2-mediated lymphangiogenesis. Inhibition of VEPTP converts ANGPT2 into a potent TIE2 activator in blood endothelium. Our data support a model whereby VEPTP functions as a rheostat to modulate ANGPT2 ligand effect on TIE2.
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30
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Han S, Lee SJ, Kim KE, Lee HS, Oh N, Park I, Ko E, Oh SJ, Lee YS, Kim D, Lee S, Lee DH, Lee KH, Chae SY, Lee JH, Kim SJ, Kim HC, Kim S, Kim SH, Kim C, Nakaoka Y, He Y, Augustin HG, Hu J, Song PH, Kim YI, Kim P, Kim I, Koh GY. Amelioration of sepsis by TIE2 activation-induced vascular protection. Sci Transl Med 2017; 8:335ra55. [PMID: 27099174 DOI: 10.1126/scitranslmed.aad9260] [Citation(s) in RCA: 159] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 02/26/2016] [Indexed: 12/13/2022]
Abstract
Protection of endothelial integrity has been recognized as a frontline approach to alleviating sepsis progression, yet no effective agent for preserving endothelial integrity is available. Using an unusual anti-angiopoietin 2 (ANG2) antibody, ABTAA (ANG2-binding and TIE2-activating antibody), we show that activation of the endothelial receptor TIE2 protects the vasculature from septic damage and provides survival benefit in three sepsis mouse models. Upon binding to ANG2, ABTAA triggers clustering of ANG2, assembling an ABTAA/ANG2 complex that can subsequently bind and activate TIE2. Compared with a conventional ANG2-blocking antibody, ABTAA was highly effective in augmenting survival from sepsis by strengthening the endothelial glycocalyx, reducing cytokine storms, vascular leakage, and rarefaction, and mitigating organ damage. Together, our data advance the role of TIE2 activation in ameliorating sepsis progression and open a potential therapeutic avenue for sepsis to address the lack of sepsis-specific treatment.
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Affiliation(s)
- Sangyeul Han
- Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea. Center for Vascular Research, Institute for Basic Science, Daejeon 305-701, Republic of Korea.
| | - Seung-Jun Lee
- Center for Vascular Research, Institute for Basic Science, Daejeon 305-701, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
| | - Kyung Eun Kim
- Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea
| | - Hyo Seon Lee
- Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea
| | - Nuri Oh
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
| | - Inwon Park
- Graduate School of Nanoscience and Technology, KAIST, Daejeon 305-701, Republic of Korea
| | - Eun Ko
- Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea
| | - Seung Ja Oh
- Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea
| | - Yoon-Sook Lee
- Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea
| | - David Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
| | - Seungjoo Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
| | - Dae Hyun Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
| | - Kwang-Hoon Lee
- Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea
| | - Su Young Chae
- Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea
| | - Jung-Hoon Lee
- Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea
| | - Su-Jin Kim
- Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea
| | - Hyung-Chan Kim
- Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea
| | - Seokkyun Kim
- Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea
| | - Sung Hyun Kim
- Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea
| | - Chungho Kim
- School of Life Sciences and Technologies, Korea University, Seoul 136-701, Republic of Korea
| | - Yoshikazu Nakaoka
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Yulong He
- Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China
| | - Hellmut G Augustin
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), 69121 Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Junhao Hu
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), 69121 Heidelberg, Germany
| | - Paul H Song
- Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea
| | - Yong-In Kim
- Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea
| | - Pilhan Kim
- Graduate School of Nanoscience and Technology, KAIST, Daejeon 305-701, Republic of Korea
| | - Injune Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
| | - Gou Young Koh
- Center for Vascular Research, Institute for Basic Science, Daejeon 305-701, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
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31
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Kim J, Park DY, Bae H, Park DY, Kim D, Lee CK, Song S, Chung TY, Lim DH, Kubota Y, Hong YK, He Y, Augustin HG, Oliver G, Koh GY. Impaired angiopoietin/Tie2 signaling compromises Schlemm's canal integrity and induces glaucoma. J Clin Invest 2017; 127:3877-3896. [PMID: 28920924 PMCID: PMC5617682 DOI: 10.1172/jci94668] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 07/18/2017] [Indexed: 12/14/2022] Open
Abstract
Primary open-angle glaucoma (POAG) is often caused by elevated intraocular pressure (IOP), which arises due to increased resistance to aqueous humor outflow (AHO). Aqueous humor flows through Schlemm's canal (SC), a lymphatic-like vessel encircling the cornea, and via intercellular spaces of ciliary muscle cells. However, the mechanisms underlying increased AHO resistance are poorly understood. Here, we demonstrate that signaling between angiopoietin (Angpt) and the Angpt receptor Tie2, which is critical for SC formation, is also indispensable for maintaining SC integrity during adulthood. Deletion of Angpt1/Angpt2 or Tie2 in adult mice severely impaired SC integrity and transcytosis, leading to elevated IOP, retinal neuron damage, and impairment of retinal ganglion cell function, all hallmarks of POAG in humans. We found that SC integrity is maintained by interconnected and coordinated functions of Angpt-Tie2 signaling, AHO, and Prox1 activity. These functions diminish in the SC during aging, leading to impaired integrity and transcytosis. Intriguingly, Tie2 reactivation using a Tie2 agonistic antibody rescued the POAG phenotype in Angpt1/Angpt2-deficient mice and rejuvenated the SC in aged mice. These results indicate that the Angpt-Tie2 system is essential for SC integrity. The impairment of this system underlies POAG-associated pathogenesis, supporting the possibility that Tie2 agonists could be a therapeutic option for glaucoma.
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Affiliation(s)
- Jaeryung Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Dae-Young Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
- Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea
- Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hosung Bae
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Do Young Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Dongkyu Kim
- Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea
| | - Choong-kun Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Sukhyun Song
- Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea
| | - Tae-Young Chung
- Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Hui Lim
- Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Department of Preventive Medicine, Catholic University School of Medicine, Seoul, Republic of Korea
| | - Yoshiaki Kubota
- The Laboratory of Vascular Biology, School of Medicine, Keio University, Tokyo, Japan
| | - Young-Kwon Hong
- Department of Surgery, Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Yulong He
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Hellmut G. Augustin
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Guillermo Oliver
- Center for Vascular and Developmental Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Gou Young Koh
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
- Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea
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32
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Bernier-Latmani J, Petrova TV. Intestinal lymphatic vasculature: structure, mechanisms and functions. Nat Rev Gastroenterol Hepatol 2017; 14:510-526. [PMID: 28655884 DOI: 10.1038/nrgastro.2017.79] [Citation(s) in RCA: 153] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The mammalian intestine is richly supplied with lymphatic vasculature, which has functions ranging from maintenance of interstitial fluid balance to transport of antigens, antigen-presenting cells, dietary lipids and fat-soluble vitamins. In this Review, we provide in-depth information concerning the organization and structure of intestinal lymphatics, the current view of their developmental origins, as well as molecular mechanisms of intestinal lymphatic patterning and maintenance. We will also discuss physiological aspects of intestinal lymph flow regulation and the known and emerging roles of intestinal lymphatic vessels in human diseases, such as IBD, infection and cancer.
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Affiliation(s)
- Jeremiah Bernier-Latmani
- Department of Fundamental Oncology, Ludwig Institute for Cancer Research and Institute of Pathology, Centre Hospitalier Universitaire Vaudois and University of Lausanne (UNIL), Chemin des Boveresses 155, Epalinges, Switzerland
| | - Tatiana V Petrova
- Department of Fundamental Oncology, Ludwig Institute for Cancer Research and Institute of Pathology, Centre Hospitalier Universitaire Vaudois and University of Lausanne (UNIL), Chemin des Boveresses 155, Epalinges, Switzerland.,Swiss Institute for Experimental Cancer Research, School of Life Sciences, Swiss Federal Institute of Technology Lausanne, Route Cantonale 1015, Lausanne, Switzerland
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33
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Angiopoietin-Tie signalling in the cardiovascular and lymphatic systems. Clin Sci (Lond) 2017; 131:87-103. [PMID: 27941161 PMCID: PMC5146956 DOI: 10.1042/cs20160129] [Citation(s) in RCA: 148] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 06/23/2016] [Accepted: 07/07/2016] [Indexed: 12/30/2022]
Abstract
Endothelial cells that form the inner layer of blood and lymphatic vessels are important regulators of vascular functions and centrally involved in the pathogenesis of vascular diseases. In addition to the vascular endothelial growth factor (VEGF) receptor pathway, the angiopoietin (Ang)-Tie system is a second endothelial cell specific ligand-receptor signalling system necessary for embryonic cardiovascular and lymphatic development. The Ang-Tie system also regulates postnatal angiogenesis, vessel remodelling, vascular permeability and inflammation to maintain vascular homoeostasis in adult physiology. This system is implicated in numerous diseases where the vasculature has an important contribution, such as cancer, sepsis, diabetes, atherosclerosis and ocular diseases. Furthermore, mutations in the TIE2 signalling pathway cause defects in vascular morphogenesis, resulting in venous malformations and primary congenital glaucoma. Here, we review recent advances in the understanding of the Ang-Tie signalling system, including cross-talk with the vascular endothelial protein tyrosine phosphatase (VE-PTP) and the integrin cell adhesion receptors, focusing on the Ang-Tie system in vascular development and pathogenesis of vascular diseases.
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34
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Park DY, Lee J, Kim J, Kim K, Hong S, Han S, Kubota Y, Augustin HG, Ding L, Kim JW, Kim H, He Y, Adams RH, Koh GY. Plastic roles of pericytes in the blood-retinal barrier. Nat Commun 2017; 8:15296. [PMID: 28508859 PMCID: PMC5440855 DOI: 10.1038/ncomms15296] [Citation(s) in RCA: 225] [Impact Index Per Article: 28.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Accepted: 03/17/2017] [Indexed: 01/18/2023] Open
Abstract
The blood-retinal barrier (BRB) consists of tightly interconnected capillary endothelial cells covered with pericytes and glia, but the role of the pericytes in BRB regulation is not fully understood. Here, we show that platelet-derived growth factor (PDGF)-B/PDGF receptor beta (PDGFRβ) signalling is critical in formation and maturation of BRB through active recruitment of pericytes onto growing retinal vessels. Impaired pericyte recruitment to the vessels shows multiple vascular hallmarks of diabetic retinopathy (DR) due to BRB disruption. However, PDGF-B/PDGFRβ signalling is expendable for maintaining BRB integrity in adult mice. Although selective pericyte loss in stable adult retinal vessels surprisingly does not cause BRB disintegration, it sensitizes retinal vascular endothelial cells (ECs) to VEGF-A, leading to upregulation of angiopoietin-2 (Ang2) in ECs through FOXO1 activation and triggering a positive feedback that resembles the pathogenesis of DR. Accordingly, either blocking Ang2 or activating Tie2 greatly attenuates BRB breakdown, suggesting potential therapeutic approaches to reduce retinal damages upon DR progression.
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Affiliation(s)
- Do Young Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
| | - Junyeop Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
| | - Jaeryung Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
| | - Kangsan Kim
- Center for Vascular Research, Institute of Basic Science (IBS), Daejeon 34141, Korea
| | - Seonpyo Hong
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
| | - Sangyeul Han
- Center for Vascular Research, Institute of Basic Science (IBS), Daejeon 34141, Korea
| | - Yoshiaki Kubota
- The Laboratory of Vascular Biology, Keio University, Tokyo 160-8582, Japan
| | - Hellmut G Augustin
- Division of Vascular Oncology and Metastasis, German Cancer Research Center, DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany
| | - Lei Ding
- Columbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA
| | - Jin Woo Kim
- Department of Biological Sciences, KAIST, Daejeon 34141, Korea
| | - Hail Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
| | - Yulong He
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China
| | - Ralf H Adams
- Department of Tissue Morphogenesis, Max-Planck-Institute for Molecular Biomedicine, and Faculty of Medicine, University of Münster, D-48149 Münster, Germany
| | - Gou Young Koh
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.,Center for Vascular Research, Institute of Basic Science (IBS), Daejeon 34141, Korea
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35
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Morooka N, Futaki S, Sato-Nishiuchi R, Nishino M, Totani Y, Shimono C, Nakano I, Nakajima H, Mochizuki N, Sekiguchi K. Polydom Is an Extracellular Matrix Protein Involved in Lymphatic Vessel Remodeling. Circ Res 2017; 120:1276-1288. [PMID: 28179430 DOI: 10.1161/circresaha.116.308825] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 01/19/2017] [Accepted: 02/07/2017] [Indexed: 12/13/2022]
Abstract
RATIONALE Lymphatic vasculature constitutes a second vascular system essential for immune surveillance and tissue fluid homeostasis. Maturation of the hierarchical vascular structure, with a highly branched network of capillaries and ducts, is crucial for its function. Environmental cues mediate the remodeling process, but the mechanism that underlies this process is largely unknown. OBJECTIVE Polydom (also called Svep1) is an extracellular matrix protein identified as a high-affinity ligand for integrin α9β1. However, its physiological function is unclear. Here, we investigated the role of Polydom in lymphatic development. METHODS AND RESULTS We generated Polydom-deficient mice. Polydom-/- mice showed severe edema and died immediately after birth because of respiratory failure. We found that although a primitive lymphatic plexus was formed, it failed to undergo remodeling in Polydom-/- embryos, including sprouting of new capillaries and formation of collecting lymphatic vessels. Impaired lymphatic development was also observed after knockdown/knockout of polydom in zebrafish. Polydom was deposited around lymphatic vessels, but secreted from surrounding mesenchymal cells. Expression of Foxc2 (forkhead box protein c2), a transcription factor involved in lymphatic remodeling, was decreased in Polydom-/- mice. Polydom bound to the lymphangiogenic factor Ang-2 (angiopoietin-2), which was found to upregulate Foxc2 expression in cultured lymphatic endothelial cells. Expressions of Tie1/Tie2 receptors for angiopoietins were also decreased in Polydom-/- mice. CONCLUSIONS Polydom affects remodeling of lymphatic vessels in both mouse and zebrafish. Polydom deposited around lymphatic vessels seems to ensure Foxc2 upregulation in lymphatic endothelial cells, possibly via the Ang-2 and Tie1/Tie2 receptor system.
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Affiliation(s)
- Nanami Morooka
- From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan
| | - Sugiko Futaki
- From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan
| | - Ryoko Sato-Nishiuchi
- From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan
| | - Masafumi Nishino
- From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan
| | - Yuta Totani
- From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan
| | - Chisei Shimono
- From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan
| | - Itsuko Nakano
- From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan
| | - Hiroyuki Nakajima
- From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan
| | - Naoki Mochizuki
- From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan
| | - Kiyotoshi Sekiguchi
- From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
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36
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Chu M, Li T, Shen B, Cao X, Zhong H, Zhang L, Zhou F, Ma W, Jiang H, Xie P, Liu Z, Dong N, Xu Y, Zhao Y, Xu G, Lu P, Luo J, Wu Q, Alitalo K, Koh GY, Adams RH, He Y. Angiopoietin receptor Tie2 is required for vein specification and maintenance via regulating COUP-TFII. eLife 2016; 5:21032. [PMID: 28005008 PMCID: PMC5218530 DOI: 10.7554/elife.21032] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2016] [Accepted: 12/21/2016] [Indexed: 12/24/2022] Open
Abstract
Mechanisms underlying the vein development remain largely unknown. Tie2 signaling mediates endothelial cell (EC) survival and vascular maturation and its activating mutations are linked to venous malformations. Here we show that vein formation are disrupted in mouse skin and mesentery when Tie2 signals are diminished by targeted deletion of Tek either ubiquitously or specifically in embryonic ECs. Postnatal Tie2 attenuation resulted in the degeneration of newly formed veins followed by the formation of haemangioma-like vascular tufts in retina and venous tortuosity. Mechanistically, Tie2 insufficiency compromised venous EC identity, as indicated by a significant decrease of COUP-TFII protein level, a key regulator in venogenesis. Consistently, angiopoietin-1 stimulation increased COUP-TFII in cultured ECs, while Tie2 knockdown or blockade of Tie2 downstream PI3K/Akt pathway reduced COUP-TFII which could be reverted by the proteasome inhibition. Together, our results imply that Tie2 is essential for venous specification and maintenance via Akt mediated stabilization of COUP-TFII.
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Affiliation(s)
- Man Chu
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Taotao Li
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Bin Shen
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.,MOE Key Laboratory for Model Animal and Disease Study, Model Animal Research Institute, Nanjing University, Nanjing, China
| | - Xudong Cao
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Haoyu Zhong
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Luqing Zhang
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.,MOE Key Laboratory for Model Animal and Disease Study, Model Animal Research Institute, Nanjing University, Nanjing, China
| | - Fei Zhou
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.,MOE Key Laboratory for Model Animal and Disease Study, Model Animal Research Institute, Nanjing University, Nanjing, China
| | - Wenjuan Ma
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Haijuan Jiang
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Pancheng Xie
- Cam-Su Genomic Resources Center, Soochow University, Suzhou, China
| | - Zhengzheng Liu
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Ningzheng Dong
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.,Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University, Suzhou, China
| | - Ying Xu
- Cam-Su Genomic Resources Center, Soochow University, Suzhou, China
| | - Yun Zhao
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.,Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University, Suzhou, China
| | - Guoqiang Xu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Peirong Lu
- The First Affiliated Hospital, Soochow University, Suzhou, China
| | - Jincai Luo
- Laboratory of Vascular Biology, Institute of Molecular Medicine, Peking University, Beijing, China
| | - Qingyu Wu
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.,Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University, Suzhou, China
| | - Kari Alitalo
- Wihuri Research Institute and Translational Cancer Biology Center of Excellence, Biomedicum Helsinki University of Helsinki, Helsinki, Finland
| | - Gou Young Koh
- Center for Vascular Research, Institute of Basic Science and Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
| | - Ralf H Adams
- Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, Faculty of Medicine, University of Münster, Münster, Germany
| | - Yulong He
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.,Cam-Su Genomic Resources Center, Soochow University, Suzhou, China.,Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
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37
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Chen L, Li J, Wang F, Dai C, Wu F, Liu X, Li T, Glauben R, Zhang Y, Nie G, He Y, Qin Z. Tie2 Expression on Macrophages Is Required for Blood Vessel Reconstruction and Tumor Relapse after Chemotherapy. Cancer Res 2016; 76:6828-6838. [PMID: 27758887 DOI: 10.1158/0008-5472.can-16-1114] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 08/18/2016] [Accepted: 09/14/2016] [Indexed: 11/16/2022]
Abstract
Tumor relapse after chemotherapy is a major hurdle for successful cancer therapy. Chemotherapeutic drugs select for resistant tumor cells and reshape tumor microenvironment, including the blood supply system. Using animal models, we observed on macrophages in tumor tissue a close correlation between upregulated Tie2 expression and tumor relapse upon chemotherapy. Conditional deletion of Tie2 expression in macrophages significantly prohibited blood supply and regrowth of tumors. Tie2+ macrophages were derived from tumor-infiltrating Tie2-CD11b+ cells and hypoxia-induced Tie2 expression on these cells. Mechanistically, expression of Tie2 prevented macrophages from apoptosis in stress conditions via the AKT-dependent signaling pathway. Together, these results demonstrate that Tie2 expression by macrophages is necessary and sufficient to promote the reconstruction of blood vessels after chemotherapy, shedding new light on developing novel strategies to inhibit tumor relapse. Cancer Res; 76(23); 6828-38. ©2016 AACR.
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Affiliation(s)
- Lin Chen
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Jie Li
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Fei Wang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Chengliang Dai
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Fan Wu
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Xiaoman Liu
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Taotao Li
- Laboratory of Vascular and Cancer Biology, Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases Thrombosis and Hemostasis Key Lab of the Ministry of Health, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, China
| | - Rainer Glauben
- Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Medical Department I, Berlin, Germany
| | - Yi Zhang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Guangjun Nie
- National Centre for Nanoscience and Technology of China, Beijing, China
| | - Yulong He
- Laboratory of Vascular and Cancer Biology, Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases Thrombosis and Hemostasis Key Lab of the Ministry of Health, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, China.
| | - Zhihai Qin
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
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38
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Sabine A, Saygili Demir C, Petrova TV. Endothelial Cell Responses to Biomechanical Forces in Lymphatic Vessels. Antioxid Redox Signal 2016; 25:451-65. [PMID: 27099026 DOI: 10.1089/ars.2016.6685] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
SIGNIFICANCE Lymphatic vessels are important components of the cardiovascular and immune systems. They contribute both to the maintenance of normal homeostasis and to many pathological conditions, such as cancer and inflammation. The lymphatic vasculature is subjected to a variety of biomechanical forces, including fluid shear stress and vessel circumferential stretch. RECENT ADVANCES This review will discuss recent advances in our understanding of biomechanical forces in lymphatic vessels and their role in mammalian lymphatic vascular development and function. CRITICAL ISSUES We will highlight the importance of fluid shear stress generated by lymph flow in organizing the lymphatic vascular network. We will also describe how mutations in mechanosensitive genes lead to lymphatic vascular dysfunction. FUTURE DIRECTIONS Better understanding of how biomechanical and biochemical stimuli are perceived and interpreted by lymphatic endothelial cells is important for targeting regulation of lymphatic function in health and disease. Important remaining critical issues and future directions in the field will be discussed in this review. Antioxid. Redox Signal. 25, 451-465.
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Affiliation(s)
- Amélie Sabine
- 1 Ludwig Institute for Cancer Research, University of Lausanne Branch & Department of Fundamental Oncology, CHUV and University of Lausanne , Epalinges, Switzerland
| | - Cansaran Saygili Demir
- 1 Ludwig Institute for Cancer Research, University of Lausanne Branch & Department of Fundamental Oncology, CHUV and University of Lausanne , Epalinges, Switzerland
| | - Tatiana V Petrova
- 1 Ludwig Institute for Cancer Research, University of Lausanne Branch & Department of Fundamental Oncology, CHUV and University of Lausanne , Epalinges, Switzerland .,2 Division of Experimental Pathology, Institute of Pathology , CHUV, Lausanne, Switzerland .,3 Swiss Institute for Experimental Cancer Research , EPFL, Switzerland
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39
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Korhonen EA, Lampinen A, Giri H, Anisimov A, Kim M, Allen B, Fang S, D'Amico G, Sipilä TJ, Lohela M, Strandin T, Vaheri A, Ylä-Herttuala S, Koh GY, McDonald DM, Alitalo K, Saharinen P. Tie1 controls angiopoietin function in vascular remodeling and inflammation. J Clin Invest 2016; 126:3495-510. [PMID: 27548530 DOI: 10.1172/jci84923] [Citation(s) in RCA: 186] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 06/24/2016] [Indexed: 12/11/2022] Open
Abstract
The angiopoietin/Tie (ANG/Tie) receptor system controls developmental and tumor angiogenesis, inflammatory vascular remodeling, and vessel leakage. ANG1 is a Tie2 agonist that promotes vascular stabilization in inflammation and sepsis, whereas ANG2 is a context-dependent Tie2 agonist or antagonist. A limited understanding of ANG signaling mechanisms and the orphan receptor Tie1 has hindered development of ANG/Tie-targeted therapeutics. Here, we determined that both ANG1 and ANG2 binding to Tie2 increases Tie1-Tie2 interactions in a β1 integrin-dependent manner and that Tie1 regulates ANG-induced Tie2 trafficking in endothelial cells. Endothelial Tie1 was essential for the agonist activity of ANG1 and autocrine ANG2. Deletion of endothelial Tie1 in mice reduced Tie2 phosphorylation and downstream Akt activation, increased FOXO1 nuclear localization and transcriptional activation, and prevented ANG1- and ANG2-induced capillary-to-venous remodeling. However, in acute endotoxemia, the Tie1 ectodomain that is responsible for interaction with Tie2 was rapidly cleaved, ANG1 agonist activity was decreased, and autocrine ANG2 agonist activity was lost, which led to suppression of Tie2 signaling. Tie1 cleavage also occurred in patients with hantavirus infection. These results support a model in which Tie1 directly interacts with Tie2 to promote ANG-induced vascular responses under noninflammatory conditions, whereas in inflammation, Tie1 cleavage contributes to loss of ANG2 agonist activity and vascular stability.
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40
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Jung M, Ören B, Mora J, Mertens C, Dziumbla S, Popp R, Weigert A, Grossmann N, Fleming I, Brüne B. Lipocalin 2 from macrophages stimulated by tumor cell-derived sphingosine 1-phosphate promotes lymphangiogenesis and tumor metastasis. Sci Signal 2016; 9:ra64. [PMID: 27353364 DOI: 10.1126/scisignal.aaf3241] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Tumor cell-derived factors skew macrophages toward a tumor-supporting phenotype associated with the secretion of protumorigenic mediators. Apoptosing tumor cells release sphingosine 1-phosphate (S1P), which stimulates the production of lipocalin 2 (LCN2) in tumor-associated macrophages and is associated with tumor metastasis. We explored the mechanism by which S1P induces LCN2 in macrophages and investigated how this contributed to tumor growth and metastasis. Knockdown of S1P receptor 1 (S1PR1) in primary human macrophages and experiments with bone marrow-derived macrophages from S1PR1-deficient mice showed that S1P signaled through S1PR1 to induce LCN2 expression. The LCN2 promoter contains a consensus sequence for signal transducer and activator of transcription 3 (STAT3), and deletion of the STAT3 recognition sequence reduced expression of an LCN2-controlled reporter gene. Conditioned medium from coculture experiments indicated that the release of LCN2 from macrophages induced tube formation and proliferation in cultures of primary human lymphatic endothelial cells in a manner dependent on the kinase PI3K and subsequent induction of the growth factor VEGFC, which functioned as an autocrine signal stimulating the receptor VEGFR3. Knockout of Lcn2 attenuated tumor-associated lymphangiogenesis and breast tumor metastasis both in the breast cancer model MMTV-PyMT mice and in mice bearing orthotopic wild-type tumors. Our findings indicate that macrophages respond to dying tumor cells by producing signals that promote lymphangiogenesis, which enables metastasis.
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Affiliation(s)
- Michaela Jung
- Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Bilge Ören
- Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Javier Mora
- Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Faculty of Microbiology, University of Costa Rica, 2060 San José, Costa Rica
| | - Christina Mertens
- Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Sarah Dziumbla
- Institute for Vascular Signalling, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Rüdiger Popp
- Institute for Vascular Signalling, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Andreas Weigert
- Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Nina Grossmann
- Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Ingrid Fleming
- Institute for Vascular Signalling, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Bernhard Brüne
- Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
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41
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Kazenwadel J, Betterman KL, Chong CE, Stokes PH, Lee YK, Secker GA, Agalarov Y, Demir CS, Lawrence DM, Sutton DL, Tabruyn SP, Miura N, Salminen M, Petrova TV, Matthews JM, Hahn CN, Scott HS, Harvey NL. GATA2 is required for lymphatic vessel valve development and maintenance. J Clin Invest 2015. [PMID: 26214525 DOI: 10.1172/jci78888] [Citation(s) in RCA: 168] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Heterozygous germline mutations in the zinc finger transcription factor GATA2 have recently been shown to underlie a range of clinical phenotypes, including Emberger syndrome, a disorder characterized by lymphedema and predisposition to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Despite well-defined roles in hematopoiesis, the functions of GATA2 in the lymphatic vasculature and the mechanisms by which GATA2 mutations result in lymphedema have not been characterized. Here, we have provided a molecular explanation for lymphedema predisposition in a subset of patients with germline GATA2 mutations. Specifically, we demonstrated that Emberger-associated GATA2 missense mutations result in complete loss of GATA2 function, with respect to the capacity to regulate the transcription of genes that are important for lymphatic vessel valve development. We identified a putative enhancer element upstream of the key lymphatic transcriptional regulator PROX1 that is bound by GATA2, and the transcription factors FOXC2 and NFATC1. Emberger GATA2 missense mutants had a profoundly reduced capacity to bind this element. Conditional Gata2 deletion in mice revealed that GATA2 is required for both development and maintenance of lymphovenous and lymphatic vessel valves. Together, our data unveil essential roles for GATA2 in the lymphatic vasculature and explain why a select catalogue of human GATA2 mutations results in lymphedema.
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42
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Chen MK, Hung MC. Proteolytic cleavage, trafficking, and functions of nuclear receptor tyrosine kinases. FEBS J 2015; 282:3693-721. [PMID: 26096795 DOI: 10.1111/febs.13342] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Revised: 05/18/2015] [Accepted: 06/09/2015] [Indexed: 01/18/2023]
Abstract
Intracellular localization has been reported for over three-quarters of receptor tyrosine kinase (RTK) families in response to environmental stimuli. Internalized RTK may bind to non-canonical substrates and affect various cellular processes. Many of the intracellular RTKs exist as fragmented forms that are generated by γ-secretase cleavage of the full-length receptor, shedding, alternative splicing, or alternative translation initiation. Soluble RTK fragments are stabilized and intracellularly transported into subcellular compartments, such as the nucleus, by binding to chaperone or transcription factors, while membrane-bound RTKs (full-length or truncated) are transported from the plasma membrane to the ER through the well-established Rab- or clathrin adaptor protein-coated vesicle retrograde trafficking pathways. Subsequent nuclear transport of membrane-bound RTK may occur via two pathways, INFS or INTERNET, with the former characterized by release of receptors from the ER into the cytosol and the latter characterized by release of membrane-bound receptor from the ER into the nucleoplasm through the inner nuclear membrane. Although most non-canonical intracellular RTK signaling is related to transcriptional regulation, there may be other functions that have yet to be discovered. In this review, we summarize the proteolytic processing, intracellular trafficking and nuclear functions of RTKs, and discuss how they promote cancer progression, and their clinical implications.
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Affiliation(s)
- Mei-Kuang Chen
- The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.,Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mien-Chie Hung
- The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.,Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Center of Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.,Department of Biotechnology, Asia University, Taichung, Taiwan
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Abstract
The endothelial TIE1 and TIE2 receptor tyrosine kinases form a distinct subfamily characterized by their unique extracellular domains. Together with the angiopoietin growth factors (ANGPT1, ANGPT2, ANGPT4, also abbreviated as ANG), the TIE receptors form an endothelial specific signaling pathway with important functions in the regulation of lymphatic and cardiovascular development and vascular homeostasis. Angiopoietins exist in multimeric forms that activate the TIE receptors via unique mechanism. In endothelial cell–cell contacts, angiopoietins induce the formation of homomeric in trans TIE receptor complexes extending across the cell junctions, whereas matrix-bound angiopoietin-1 (ANG1) activates the TIE receptors in a cis configuration. In comparison to the vascular endothelial growth factor receptors, the TIE receptors undergo little ubiquitin-mediated degradation after activation, whereas TIE2 signaling is negatively regulated by the vascular endothelial protein tyrosine phosphatase, VE-PTP. ANG1 activation of TIE2 supports vascular stabilization, whereas angiopoietin-2 (ANG2), a context-dependent weak TIE2 agonist/antagonist, promotes pathological tumor angiogenesis, vascular permeability, and inflammation. Recently, ANG2 has been found to mediate some of its vascular destabilizing and angiogenic functions via integrin signalling. The circulating levels of ANG2 are increased in cancer, and in several human diseases associated with inflammation and vascular leak, for example, in sepsis. Blocking of ANG2 has emerged as a potential novel therapeutic strategy for these diseases. In addition, preclinical results demonstrate that genetic TIE1 deletion in mice inhibits the vascularization and growth of tumor isografts and protects from atherosclerosis, with little effect on normal vascular homeostasis in adult mice. The ability of the ANG-TIE pathway to control vessel stability and angiogenesis makes it an interesting vascular target for the treatment of the various diseases.
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Qu X, Zhou B, Scott Baldwin H. Tie1 is required for lymphatic valve and collecting vessel development. Dev Biol 2015; 399:117-128. [PMID: 25576926 DOI: 10.1016/j.ydbio.2014.12.021] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 12/10/2014] [Accepted: 12/17/2014] [Indexed: 12/29/2022]
Abstract
Tie1 is a receptor tyrosine kinase with broad expression in embryonic endothelium. Reduction of Tie1 levels in mouse embryos with a hypomorphic Tie1 allele resulted in abnormal lymphatic patterning and architecture, decreased lymphatic draining efficiency, and ultimately, embryonic demise. Here we report that Tie1 is present uniformly throughout the lymphatics and from late embryonic/early postnatal stages, becomes more restricted to lymphatic valve regions. To investigate later events of lymphatic development, we employed Cre-loxP recombination utilizing a floxed Tie1 allele and an Nfatc1Cre line, to provide loxP excision predominantly in lymphatic endothelium and developing valves. Interestingly, unlike the early prenatal defects previously described by ubiquitous endothelial deletion, excision of Tie1 with Nfatc1Cre resulted in abnormal lymphatic defects in postnatal mice and was characterized by agenesis of lymphatic valves and a deficiency of collecting lymphatic vessels. Attenuation of Tie1 signaling in lymphatic endothelium prevented initiation of lymphatic valve specification by Prox1 high expression lymphatic endothelial cells that is associated with the onset of turbulent flow in the lymphatic circulation. Our findings reveal a fundamental role for Tie1 signaling during lymphatic vessel remodeling and valve morphogenesis and implicate it as a candidate gene involved in primary lymphedema.
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Affiliation(s)
- Xianghu Qu
- Department of Pediatrics (Cardiology), Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Bin Zhou
- Department of Genetics, Albert Einstein College of Medicine, NY 10461, USA
| | - H Scott Baldwin
- Department of Pediatrics (Cardiology), Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Development Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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Bazigou E, Wilson JT, Moore JE. Primary and secondary lymphatic valve development: molecular, functional and mechanical insights. Microvasc Res 2014; 96:38-45. [PMID: 25086182 DOI: 10.1016/j.mvr.2014.07.008] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Revised: 07/17/2014] [Accepted: 07/22/2014] [Indexed: 01/27/2023]
Abstract
Fluid homeostasis in vertebrates critically relies on the lymphatic system forming a hierarchical network of lymphatic capillaries and collecting lymphatics, for the efficient drainage and transport of extravasated fluid back to the cardiovascular system. Blind-ended lymphatic capillaries employ specialized junctions and anchoring filaments to encourage a unidirectional flow of the interstitial fluid into the initial lymphatic vessels, whereas collecting lymphatics are responsible for the active propulsion of the lymph to the venous circulation via the combined action of lymphatic muscle cells and intraluminal valves. Here we describe recent findings on molecular and physical factors regulating the development and maturation of these two types of valves and examine their role in tissue-fluid homeostasis.
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Affiliation(s)
- Eleni Bazigou
- Department of Bioengineering, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
| | - John T Wilson
- Department of Bioengineering, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
| | - James E Moore
- Department of Bioengineering, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
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