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  • 1
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    Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-07-03
    Description: Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is a key process in several pathological conditions, including tumour growth and age-related macular degeneration. Vascular endothelial growth factors (VEGFs) stimulate angiogenesis and lymphangiogenesis by activating VEGF receptor (VEGFR) tyrosine kinases in endothelial cells. VEGFR-3 (also known as FLT-4) is present in all endothelia during development, and in the adult it becomes restricted to the lymphatic endothelium. However, VEGFR-3 is upregulated in the microvasculature of tumours and wounds. Here we demonstrate that VEGFR-3 is highly expressed in angiogenic sprouts, and genetic targeting of VEGFR-3 or blocking of VEGFR-3 signalling with monoclonal antibodies results in decreased sprouting, vascular density, vessel branching and endothelial cell proliferation in mouse angiogenesis models. Stimulation of VEGFR-3 augmented VEGF-induced angiogenesis and sustained angiogenesis even in the presence of VEGFR-2 (also known as KDR or FLK-1) inhibitors, whereas antibodies against VEGFR-3 and VEGFR-2 in combination resulted in additive inhibition of angiogenesis and tumour growth. Furthermore, genetic or pharmacological disruption of the Notch signalling pathway led to widespread endothelial VEGFR-3 expression and excessive sprouting, which was inhibited by blocking VEGFR-3 signals. Our results implicate VEGFR-3 as a regulator of vascular network formation. Targeting VEGFR-3 may provide additional efficacy for anti-angiogenic therapies, especially towards vessels that are resistant to VEGF or VEGFR-2 inhibitors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tammela, Tuomas -- Zarkada, Georgia -- Wallgard, Elisabet -- Murtomaki, Aino -- Suchting, Steven -- Wirzenius, Maria -- Waltari, Marika -- Hellstrom, Mats -- Schomber, Tibor -- Peltonen, Reetta -- Freitas, Catarina -- Duarte, Antonio -- Isoniemi, Helena -- Laakkonen, Pirjo -- Christofori, Gerhard -- Yla-Herttuala, Seppo -- Shibuya, Masabumi -- Pytowski, Bronislaw -- Eichmann, Anne -- Betsholtz, Christer -- Alitalo, Kari -- 5 R01 HL075183-02/HL/NHLBI NIH HHS/ -- England -- Nature. 2008 Jul 31;454(7204):656-60. doi: 10.1038/nature07083. Epub 2008 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and the Haartman Institute University of Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 Helsinki, Finland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18594512" target="_blank"〉PubMed〈/a〉
    Keywords: Angiogenesis Inhibitors/pharmacology ; Animals ; Antibodies, Monoclonal/pharmacology ; Cell Line, Tumor ; Dipeptides/pharmacology ; Down-Regulation ; Endothelial Cells/metabolism ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Ligands ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic ; Neoplasms/*blood supply/drug therapy ; Neovascularization, Pathologic/genetics/*metabolism ; Receptors, Notch/metabolism ; Signal Transduction ; Vascular Endothelial Growth Factor Receptor-3/*antagonists & ; inhibitors/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Pericytes regulate the blood-brain barrier (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-10-15
    Description: The blood-brain barrier (BBB) consists of specific physical barriers, enzymes and transporters, which together maintain the necessary extracellular environment of the central nervous system (CNS). The main physical barrier is found in the CNS endothelial cell, and depends on continuous complexes of tight junctions combined with reduced vesicular transport. Other possible constituents of the BBB include extracellular matrix, astrocytes and pericytes, but the relative contribution of these different components to the BBB remains largely unknown. Here we demonstrate a direct role of pericytes at the BBB in vivo. Using a set of adult viable pericyte-deficient mouse mutants we show that pericyte deficiency increases the permeability of the BBB to water and a range of low-molecular-mass and high-molecular-mass tracers. The increased permeability occurs by endothelial transcytosis, a process that is rapidly arrested by the drug imatinib. Furthermore, we show that pericytes function at the BBB in at least two ways: by regulating BBB-specific gene expression patterns in endothelial cells, and by inducing polarization of astrocyte end-feet surrounding CNS blood vessels. Our results indicate a novel and critical role for pericytes in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the BBB.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Armulik, Annika -- Genove, Guillem -- Mae, Maarja -- Nisancioglu, Maya H -- Wallgard, Elisabet -- Niaudet, Colin -- He, Liqun -- Norlin, Jenny -- Lindblom, Per -- Strittmatter, Karin -- Johansson, Bengt R -- Betsholtz, Christer -- England -- Nature. 2010 Nov 25;468(7323):557-61. doi: 10.1038/nature09522. Epub 2010 Oct 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Scheeles vag 2, SE-171 77 Stockholm, Sweden. annika.armulik@ki.se〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20944627" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Astrocytes/metabolism ; Benzamides ; Blood-Brain Barrier/*cytology/*metabolism ; Central Nervous System/blood supply ; Endothelial Cells/metabolism ; Gene Expression Regulation ; Imatinib Mesylate ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Pericytes/*metabolism ; Piperazines/pharmacology ; Protein Kinase Inhibitors/pharmacology ; Pyrimidines/pharmacology ; Transcytosis/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Apolipoprotein E controls cerebrovascular integrity via cyclophilin A (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-05-25
    Description: Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE4. APOE4 is a major genetic risk factor for Alzheimer's disease and is associated with Down's syndrome dementia and poor neurological outcome after traumatic brain injury and haemorrhage. Neurovascular dysfunction is present in normal APOE4 carriers and individuals with APOE4-associated disorders. In mice, lack of Apoe leads to blood-brain barrier (BBB) breakdown, whereas APOE4 increases BBB susceptibility to injury. How APOE genotype affects brain microcirculation remains elusive. Using different APOE transgenic mice, including mice with ablation and/or inhibition of cyclophilin A (CypA), here we show that expression of APOE4 and lack of murine Apoe, but not APOE2 and APOE3, leads to BBB breakdown by activating a proinflammatory CypA-nuclear factor-kappaB-matrix-metalloproteinase-9 pathway in pericytes. This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. We show that the vascular defects in Apoe-deficient and APOE4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted APOE3, but not APOE4, suppressed the CypA-nuclear factor-kappaB-matrix-metalloproteinase-9 pathway in pericytes through a lipoprotein receptor. Our data suggest that CypA is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047116/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047116/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bell, Robert D -- Winkler, Ethan A -- Singh, Itender -- Sagare, Abhay P -- Deane, Rashid -- Wu, Zhenhua -- Holtzman, David M -- Betsholtz, Christer -- Armulik, Annika -- Sallstrom, Jan -- Berk, Bradford C -- Zlokovic, Berislav V -- R01 AG039452/AG/NIA NIH HHS/ -- R01 NS034467/NS/NINDS NIH HHS/ -- R01AG039452/AG/NIA NIH HHS/ -- R37 AG013956/AG/NIA NIH HHS/ -- R37 AG023084/AG/NIA NIH HHS/ -- R37 NS034467/NS/NINDS NIH HHS/ -- R37AG13956/AG/NIA NIH HHS/ -- R37AG23084/AG/NIA NIH HHS/ -- R37NS34467/NS/NINDS NIH HHS/ -- England -- Nature. 2012 May 16;485(7399):512-6. doi: 10.1038/nature11087.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester Medical Center, Rochester, New York 14642, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22622580" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apolipoprotein E2/deficiency/genetics/metabolism ; Apolipoprotein E3/deficiency/genetics/metabolism ; Apolipoprotein E4/deficiency/genetics/metabolism ; Apolipoproteins E/deficiency/genetics/*metabolism ; Blood-Brain Barrier/drug effects/*physiology/physiopathology ; Cerebrovascular Circulation/*physiology ; Cyclophilin A/antagonists & inhibitors/deficiency/*metabolism ; Hippocampus/metabolism/pathology ; Humans ; Matrix Metalloproteinase 9/metabolism ; Mice ; Mice, Transgenic ; Microcirculation ; NF-kappa B/metabolism ; Neurodegenerative Diseases/metabolism/pathology ; Neurons/metabolism/pathology ; Pericytes/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Vascular biology: Transcriptional control of endothelial energy (2016)
    Nature Publishing Group (NPG)
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    Publication Date: 2016-01-07
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Betsholtz, Christer -- England -- Nature. 2016 Jan 14;529(7585):160-1. doi: 10.1038/nature16866. Epub 2016 Jan 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, Genetics and Pathology at Uppsala University, and the Department of Medical Biochemistry and Biophysics at the Karolinska Institutet, Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26735011" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Endothelium, Vascular/*growth & development/*metabolism ; Female ; Forkhead Transcription Factors/*metabolism ; Humans ; Male
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    Age-dependent modulation of vascular niches for haematopoietic stem cells (2016)
    Nature Publishing Group (NPG)
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    Publication Date: 2016-04-14
    Description: Blood vessels define local microenvironments in the skeletal system, play crucial roles in osteogenesis and provide niches for haematopoietic stem cells. The properties of niche-forming vessels and their changes in the ageing organism remain incompletely understood. Here we show that Notch signalling in endothelial cells leads to the expansion of haematopoietic stem cell niches in bone, which involves increases in CD31-positive capillaries and platelet-derived growth factor receptor-beta (PDGFRbeta)-positive perivascular cells, arteriole formation and elevated levels of cellular stem cell factor. Although endothelial hypoxia-inducible factor signalling promotes some of these changes, it fails to enhance vascular niche function because of a lack of arterialization and expansion of PDGFRbeta-positive cells. In ageing mice, niche-forming vessels in the skeletal system are strongly reduced but can be restored by activation of endothelial Notch signalling. These findings indicate that vascular niches for haematopoietic stem cells are part of complex, age-dependent microenvironments involving multiple cell populations and vessel subtypes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kusumbe, Anjali P -- Ramasamy, Saravana K -- Itkin, Tomer -- Mae, Maarja Andaloussi -- Langen, Urs H -- Betsholtz, Christer -- Lapidot, Tsvee -- Adams, Ralf H -- England -- Nature. 2016 Apr 21;532(7599):380-4. doi: 10.1038/nature17638. Epub 2016 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Munster, Faculty of Medicine, D-48149 Munster, Germany. ; Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel. ; Vascular Biology Program, Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden. ; Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Scheeles vag 2, SE-171 77 Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27074508" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/*physiology ; Animals ; Antigens, CD31/metabolism ; Arterioles/cytology/*physiology ; Bone and Bones/*blood supply/cytology/metabolism ; Capillaries/cytology/*physiology ; Cell Count ; Endothelial Cells/metabolism ; Hematopoietic Stem Cells/*cytology ; Hypoxia-Inducible Factor 1/metabolism ; Male ; Mice ; Osteogenesis ; Receptor, Platelet-Derived Growth Factor beta/metabolism ; Receptors, Notch/metabolism ; Signal Transduction ; Stem Cell Factor/metabolism ; *Stem Cell Niche
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    Physiology: Double function at the blood-brain barrier (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-05-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Betsholtz, Christer -- England -- Nature. 2014 May 22;509(7501):432-3. doi: 10.1038/nature13339. Epub 2014 May 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala 75185, Sweden, and the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24828036" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blood-Brain Barrier/*embryology/*physiology ; Brain/*metabolism ; Docosahexaenoic Acids/*metabolism ; Female ; Male ; Membrane Transport Proteins/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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