Dietary Vitamin D and Its Metabolites Non-Genomically Stabilize the Endothelium
Publication Date
October 15, 2015
Journal
PLOS ONE
Authors
Christopher C. Gibson, Chadwick T. Davis, Weiquan Zhu, Jay A. Bowman Kirigin, et al
Volume
10
Issue
10
Pages
e0140370
DOI
https://dx.plos.org/10.1371/journal.pone.0140370
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0140370
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/26469335
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607301
Europe PMC
http://europepmc.org/abstract/MED/26469335
Web of Science
000363184600052
Scopus
84948953775
Mendeley
http://www.mendeley.com/research/dietary-vitamin-d-metabolites-nongenomically-stabilize-endothelium
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Mendeley | Further Information

{"title"=>"Dietary Vitamin D and its metabolites non-genomically stabilize the endothelium", "type"=>"journal", "authors"=>[{"first_name"=>"Christopher C.", "last_name"=>"Gibson", "scopus_author_id"=>"36816007200"}, {"first_name"=>"Chadwick T.", "last_name"=>"Davis", "scopus_author_id"=>"55453920700"}, {"first_name"=>"Weiquan", "last_name"=>"Zhu", "scopus_author_id"=>"55483177800"}, {"first_name"=>"Jay A.", "last_name"=>"Bowman-Kirigin", "scopus_author_id"=>"56200558500"}, {"first_name"=>"Ashley E.", "last_name"=>"Walker", "scopus_author_id"=>"16032129300"}, {"first_name"=>"Zhengfu", "last_name"=>"Tai", "scopus_author_id"=>"54399281100"}, {"first_name"=>"Kirk R.", "last_name"=>"Thomas", "scopus_author_id"=>"7402627130"}, {"first_name"=>"Anthony J.", "last_name"=>"Donato", "scopus_author_id"=>"7005363211"}, {"first_name"=>"Lisa A.", "last_name"=>"Lesniewski", "scopus_author_id"=>"6506983951"}, {"first_name"=>"Dean Y.", "last_name"=>"Li", "scopus_author_id"=>"24284763700"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"26469335", "doi"=>"10.1371/journal.pone.0140370", "sgr"=>"84948953775", "scopus"=>"2-s2.0-84948953775", "issn"=>"19326203", "pui"=>"607111787"}, "id"=>"04884da7-487e-35a8-9fcc-193581e475be", "abstract"=>"Vitamin D is a known modulator of inflammation. Native dietary vitamin D3 is thought to be bio-inactive, and beneficial vitamin D3 effects are thought to be largely mediated by the metabolite 1,25(OH)2D3. Reduced serum levels of the most commonly measured precursor metabolite, 25(OH)D3, is linked to an increased risk of multiple inflammatory diseases, including: cardiovascular disease, arthritis, multiple sclerosis, and sepsis. Common to all of these diseases is the disruption of endothelial stability and an enhancement of vascular leak. We previously performed an unbiased chemical suppressor screen on a genetic model of vascular instability, and identified cholecalciferol (D3, dietary Vitamin D3) as a factor that had profound and immediate stabilizing and therapeutic effects in that model. In this manuscript we show that the presumed inactive sterol, D3, is actually a potent and general mediator of endothelial stability at physiologically relevant concentrations. We further demonstrate that this phenomenon is apparent in vitamin D3 metabolites 25(OH)D3 and 1,25(OH)2D3, and that the effects are independent of the canonical transcription-mediated vitamin D pathway. Our data suggests the presence of an alternative signaling modality by which D3 acts directly on endothelial cells to prevent vascular leak. The finding that D3 and its metabolites modulate endothelial stability may help explain the clinical correlations between low serum vitamin D levels and the many human diseases with well-described vascular dysfunction phenotypes.", "link"=>"http://www.mendeley.com/research/dietary-vitamin-d-metabolites-nongenomically-stabilize-endothelium", "reader_count"=>19, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Librarian"=>1, "Researcher"=>3, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>1, "Student > Postgraduate"=>1, "Other"=>3, "Student > Master"=>4, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Librarian"=>1, "Researcher"=>3, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>1, "Student > Postgraduate"=>1, "Other"=>3, "Student > Master"=>4, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Engineering"=>2, "Biochemistry, Genetics and Molecular Biology"=>2, "Nursing and Health Professions"=>1, "Medicine and Dentistry"=>5, "Agricultural and Biological Sciences"=>3, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Immunology and Microbiology"=>1, "Economics, Econometrics and Finance"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>2}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Economics, Econometrics and Finance"=>{"Economics, Econometrics and Finance"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>3}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}}, "reader_count_by_country"=>{"Belgium"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2360956"], "description"=>"<p>Dose/time resistance (endothelial stability) surfaces generated with ECIS are shown from 100 pM to 10 μM and from zero to 21 hours for: (<b>A</b>) D<sub>3</sub>; (<b>F</b>) 25(OH)D<sub>3</sub>; (<b>K</b>) 1,25(OH)<sub>2</sub>D<sub>3</sub>. Detailed time-responses are shown at 1 nM and 10 μM respectively for: (<b>B</b> and <b>C)</b> D<sub>3</sub>; (<b>G</b> and <b>H</b>) 25(OH)D<sub>3</sub>; and (<b>L</b> and <b>M</b>) 1,25(OH)<sub>2</sub>D<sub>3</sub>. Detailed dose-response are shown at 4 hours and 12 hours respectively for (<b>D</b> and <b>E)</b> D<sub>3</sub>, (<b>I</b> and <b>J</b>) 25(OH)D<sub>3</sub>, and (<b>N</b> and <b>O</b>) 1,25(OH)<sub>2</sub>D<sub>3</sub>.</p>", "links"=>[], "tags"=>["stability", "D 3 acts", "precursor metabolite", "leak", "serum Vitamin D levels", "dysfunction phenotypes", "Dietary Vitamin D", "model", "Endothelium Vitamin D", "vitamin D 3 effects", "chemical suppressor screen", "oh", "D 3", "Vitamin D 3"], "article_id"=>1576528, "categories"=>["Uncategorised"], "users"=>["Christopher C. Gibson", "Chadwick T. Davis", "Weiquan Zhu", "Jay A. Bowman-Kirigin", "Ashley E. Walker", "Zhengfu Tai", "Kirk R. Thomas", "Anthony J. Donato", "Lisa A. Lesniewski", "Dean Y. Li"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0140370.g001", "stats"=>{"downloads"=>2, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Vitamin_D_stabilizes_the_endothelium_/1576528", "title"=>"Vitamin D stabilizes the endothelium.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-15 02:48:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/2360973", "https://ndownloader.figshare.com/files/2360974"], "description"=>"<div><p>Vitamin D is a known modulator of inflammation. Native dietary vitamin D<sub>3</sub> is thought to be bio-inactive, and beneficial vitamin D<sub>3</sub> effects are thought to be largely mediated by the metabolite 1,25(OH)<sub>2</sub>D<sub>3</sub>. Reduced serum levels of the most commonly measured precursor metabolite, 25(OH)D<sub>3</sub>, is linked to an increased risk of multiple inflammatory diseases, including: cardiovascular disease, arthritis, multiple sclerosis, and sepsis. Common to all of these diseases is the disruption of endothelial stability and an enhancement of vascular leak. We previously performed an unbiased chemical suppressor screen on a genetic model of vascular instability, and identified cholecalciferol (D<sub>3</sub>, dietary Vitamin D<sub>3</sub>) as a factor that had profound and immediate stabilizing and therapeutic effects in that model. In this manuscript we show that the presumed inactive sterol, D<sub>3</sub>, is actually a potent and general mediator of endothelial stability at physiologically relevant concentrations. We further demonstrate that this phenomenon is apparent in vitamin D<sub>3</sub> metabolites 25(OH)D<sub>3</sub> and 1,25(OH)<sub>2</sub>D<sub>3</sub>, and that the effects are independent of the canonical transcription-mediated vitamin D pathway. Our data suggests the presence of an alternative signaling modality by which D<sub>3</sub> acts directly on endothelial cells to prevent vascular leak. The finding that D<sub>3</sub> and its metabolites modulate endothelial stability may help explain the clinical correlations between low serum vitamin D levels and the many human diseases with well-described vascular dysfunction phenotypes.</p></div>", "links"=>[], "tags"=>["stability", "D 3 acts", "precursor metabolite", "leak", "serum Vitamin D levels", "dysfunction phenotypes", "Dietary Vitamin D", "model", "Endothelium Vitamin D", "vitamin D 3 effects", "chemical suppressor screen", "oh", "D 3", "Vitamin D 3"], "article_id"=>1576545, "categories"=>["Uncategorised"], "users"=>["Christopher C. Gibson", "Chadwick T. Davis", "Weiquan Zhu", "Jay A. Bowman-Kirigin", "Ashley E. Walker", "Zhengfu Tai", "Kirk R. Thomas", "Anthony J. Donato", "Lisa A. Lesniewski", "Dean Y. Li"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0140370.s001", "https://dx.doi.org/10.1371/journal.pone.0140370.s002"], "stats"=>{"downloads"=>5, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dietary_Vitamin_D_and_Its_Metabolites_Non_Genomically_Stabilize_the_Endothelium_/1576545", "title"=>"Dietary Vitamin D and Its Metabolites Non-Genomically Stabilize the Endothelium", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-10-15 02:48:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/2360958"], "description"=>"<p>Monolayers of HMVEC were stimulated with D<sub>3</sub> (10 μM), 7-DHC(10 μM), or 0.5% DMSO (vehicle control) in the presence of inflammatory cytokines: IL-1β (10 ng/mL), TNF-α (2 ng/mL), and LPS (100 ng/mL) in an (<b>A-C</b>) ECIS or (<b>D</b>) transwell leak assay. (<b>E</b>) VEGF-induced leak of a fluorescent reporter in arterioles isolated from wild-type mice fed either standard chow or a D<sub>3</sub>-enhanced chow. All panels depict mean ± SEM. * denotes P<0.05, ** denotes P<0.01, and **** denotes P<0.0001.</p>", "links"=>[], "tags"=>["stability", "D 3 acts", "precursor metabolite", "leak", "serum Vitamin D levels", "dysfunction phenotypes", "Dietary Vitamin D", "model", "Endothelium Vitamin D", "vitamin D 3 effects", "chemical suppressor screen", "oh", "D 3", "Vitamin D 3"], "article_id"=>1576530, "categories"=>["Uncategorised"], "users"=>["Christopher C. Gibson", "Chadwick T. Davis", "Weiquan Zhu", "Jay A. Bowman-Kirigin", "Ashley E. Walker", "Zhengfu Tai", "Kirk R. Thomas", "Anthony J. Donato", "Lisa A. Lesniewski", "Dean Y. Li"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0140370.g002", "stats"=>{"downloads"=>5, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_D_3_abrogates_inflammatory_leak_in_culture_and_ex_vivo_/1576530", "title"=>"D<sub>3</sub> abrogates inflammatory leak in culture and <i>ex</i> vivo.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-15 02:48:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/2360960"], "description"=>"<p>Endothelial cells were exposed to 10 μM D<sub>3</sub> or 7-DHC in combination with 2ng/mL TNF-α or IL-1β. Lysates were analyzed for RHOA-GTP and ARF6-GTP levels using appropriate precipitation assays. All graphs depict mean ± SEM. * denotes P<0.05, ** denotes P<0.01, and *** denotes P<0.001.</p>", "links"=>[], "tags"=>["stability", "D 3 acts", "precursor metabolite", "leak", "serum Vitamin D levels", "dysfunction phenotypes", "Dietary Vitamin D", "model", "Endothelium Vitamin D", "vitamin D 3 effects", "chemical suppressor screen", "oh", "D 3", "Vitamin D 3"], "article_id"=>1576532, "categories"=>["Uncategorised"], "users"=>["Christopher C. Gibson", "Chadwick T. Davis", "Weiquan Zhu", "Jay A. Bowman-Kirigin", "Ashley E. Walker", "Zhengfu Tai", "Kirk R. Thomas", "Anthony J. Donato", "Lisa A. Lesniewski", "Dean Y. Li"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0140370.g003", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_D_3_blocks_RHOA_and_ARF6_activation_in_destabilized_endothelial_cells_/1576532", "title"=>"D<sub>3</sub> blocks RHOA and ARF6 activation in destabilized endothelial cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-15 02:48:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/2360963"], "description"=>"<p>(<b>A</b>) Endothelial cells were treated with TNF-α and either 7-DHC or D<sub>3</sub> for the denoted times and lysates were immunoblotted for p731 VE-cadherin or total VE-Cadherin. (<b>B</b>) Endothelial cell monolayers were exposed to the denoted pro-inflammatory cues in the presence of vehicle control, D<sub>3</sub> or 7DHC. Cells were fixed and VE-Cadherin was visualized through immunofluorescent labeling with automated image acquisition and analysis. All graphs depict mean ± SEM. * denotes P<0.05, ** denotes P<0.01, and *** denotes P<0.001.</p>", "links"=>[], "tags"=>["stability", "D 3 acts", "precursor metabolite", "leak", "serum Vitamin D levels", "dysfunction phenotypes", "Dietary Vitamin D", "model", "Endothelium Vitamin D", "vitamin D 3 effects", "chemical suppressor screen", "oh", "D 3", "Vitamin D 3"], "article_id"=>1576535, "categories"=>["Uncategorised"], "users"=>["Christopher C. Gibson", "Chadwick T. Davis", "Weiquan Zhu", "Jay A. Bowman-Kirigin", "Ashley E. Walker", "Zhengfu Tai", "Kirk R. Thomas", "Anthony J. Donato", "Lisa A. Lesniewski", "Dean Y. Li"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0140370.g004", "stats"=>{"downloads"=>2, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_D_3_promotes_VE_cadherin_cell_cell_junction_stability_/1576535", "title"=>"D<sub>3</sub> promotes VE-cadherin cell-cell junction stability.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-15 02:48:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/2360965"], "description"=>"<p><b>(A)</b> Endothelial cells were exposed to D<sub>3</sub> or its metabolites for 24 hours and lysates were probed for VDR transcription targets FOX01 and CYP24. Endothelial cells were exposed to D<sub>3</sub> or its metabolites in the presence of inhibitors of transcription (actinomycin D) and translation (cycloheximide) <b>(B, C)</b> and were assessed for transendothelial resistance or VDR target gene expression. All graphs depict mean ± SEM. * denotes P<0.05, and **** denotes P<0.0001. ### denotes P<0.001, and #### denotes P<0.0001 versus the respective control.</p>", "links"=>[], "tags"=>["stability", "D 3 acts", "precursor metabolite", "leak", "serum Vitamin D levels", "dysfunction phenotypes", "Dietary Vitamin D", "model", "Endothelium Vitamin D", "vitamin D 3 effects", "chemical suppressor screen", "oh", "D 3", "Vitamin D 3"], "article_id"=>1576537, "categories"=>["Uncategorised"], "users"=>["Christopher C. Gibson", "Chadwick T. Davis", "Weiquan Zhu", "Jay A. Bowman-Kirigin", "Ashley E. Walker", "Zhengfu Tai", "Kirk R. Thomas", "Anthony J. Donato", "Lisa A. Lesniewski", "Dean Y. Li"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0140370.g005", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_D_3_stabilizes_endothelial_cells_through_a_non_genomic_mechanism_/1576537", "title"=>"D<sub>3</sub> stabilizes endothelial cells through a non-genomic mechanism.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-15 02:48:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/2360966"], "description"=>"<p>Graphical models of the different vitamin D3 sterols, their metabolism, and a summary of their normal circulating levels, the minimum active dose for stabilizing the endothelium and doses in which the sterols have been reported to interact with vitamin D receptor [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140370#pone.0140370.ref029\" target=\"_blank\">29</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140370#pone.0140370.ref051\" target=\"_blank\">51</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140370#pone.0140370.ref052\" target=\"_blank\">52</a>]. *Normal circulating levels vary upon many conditions including diet and UV exposure.</p>", "links"=>[], "tags"=>["stability", "D 3 acts", "precursor metabolite", "leak", "serum Vitamin D levels", "dysfunction phenotypes", "Dietary Vitamin D", "model", "Endothelium Vitamin D", "vitamin D 3 effects", "chemical suppressor screen", "oh", "D 3", "Vitamin D 3"], "article_id"=>1576538, "categories"=>["Uncategorised"], "users"=>["Christopher C. Gibson", "Chadwick T. Davis", "Weiquan Zhu", "Jay A. Bowman-Kirigin", "Ashley E. Walker", "Zhengfu Tai", "Kirk R. Thomas", "Anthony J. Donato", "Lisa A. Lesniewski", "Dean Y. Li"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0140370.g006", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Vitamin_D_sterol_activity_/1576538", "title"=>"Vitamin D sterol activity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-15 02:48:07"}

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Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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