Inhibition of VE‐Cadherin Proteasomal Degradation Attenuates Microvascular Hyperpermeability
Identifieur interne : 001551 ( Main/Exploration ); précédent : 001550; suivant : 001552Inhibition of VE‐Cadherin Proteasomal Degradation Attenuates Microvascular Hyperpermeability
Auteurs : Devendra A. Sawant [États-Unis] ; Binu Tharakan [États-Unis] ; Ashton Adekanbi [États-Unis] ; Felicia A. Hunter [États-Unis] ; William Roy Smythe [États-Unis] ; Ed W. Childs [États-Unis]Source :
- Microcirculation [ 1073-9688 ] ; 2011-01.
English descriptors
- Teeft :
- Adherens, Adherens junction, Adherens junctional, Adherens junctions, Binding sites, Blood volume, Blue color, Bronectin, Cadherin, Chloroquine, Chloroquine diphosphate, Competitive binding, Complete media, Control cells, Control group, Control monolayers, Control transit, Control values, Cytoplasmic, Cytoplasmic levels, Cytoskeletal, Cytoskeletal assembly, Dapi staining, Degradation, Endogenous, Endothelial, Endothelial cells, Extracellular, Extracellular domain, Extravasation, Extravascular space, Glass bottom dishes, Hyperpermeability, Immunoblot analysis, Inhibitor, John wiley sons, Junctional, Junctional damage, Luciferase, Luciferase activity, Luciferase reporter assay, Lung microvascular, Lysosomal, Lysosomal inhibitor, Mesenteric postcapillary venules, Microcirculation, Microvascular, Microvascular hyperpermeability, Monolayer, Monolayer hyperpermeability, Monolayer permeability, Monolayers, Mutant, Mutant protein, Optical intensity, Parallel studies, Pathway, Permeability, Physiol, Polyclonal antibody, Postcapillary, Proteasomal, Proteasomal degradation, Proteasomal inhibitor, Proteasome, Proteasome inhibitor, Protein levels, Reagent, Recombinant, Recombinant cytoplasmic domain, Rhodamine phalloidin, Room temperature, Santa cruz biotechnology, Sirna, Transcriptional, Transcriptional activation, Transcriptional activity, Transfected, Transfected cells, Transfected group, Transfection, Transfection reagent, Transwell plates, Untreated, Untreated control cells, Untreated control group, Untreated monolayers, Uorescent, Uorescent intensity, Uorometric plate reader, Vascular, Vascular hyperpermeability, Vascular permeability, Venule.
Abstract
Please cite this paper as: Sawant, Tharakan, Adekanbi, Hunter, Smythe and Childs (2011). Inhibition of VE‐Cadherin Proteasomal Degradation Attenuates Microvascular Hyperpermeability. Microcirculation18(1), 46–55. Abstract: Objective: VE‐cadherin, an integral component of the adherens junction complex, is processed through the endosome–lysosome pathway and proteasome system for degradation. Our objective was to determine if inhibition of this pathway would protect against microvascular hyperpermeability. Methods: To induce VE‐cadherin degradation, we utilized a mutant VE‐cadherin protein that lacks the extracellular domain (rVE‐cad CPD). Intravital microscopy was employed to study the changes in microvascular permeability in rat mesenteric postcapillary venules. Rat lung microvascular endothelial cell (RLMEC) monolayers were utilized in parallel studies. The adherens junction integrity was determined using VE‐cadherin and β‐catenin immunofluorescence. TOPflash/FOPflash transfection and luciferase reporter assay were performed to study β‐catenin‐mediated transcriptional activation. Results: rVE‐cad CPD (2.5 μg/mL of blood volume) increased hyperpermeability significantly (p < 0.05). The VE‐cadherin siRNA as well as rVE‐cad CPD induced significant increase in monolayer hyperpermeability (p < 0.05). Transfection of rVE‐cad CPD disrupted adherens junctions evidenced by discontinuity in β‐catenin and VE‐cadherin immunofluorescence (p < 0.05). Proteasome inhibitor MG132 attenuated rVE‐cad CPD induced monolayer hyperpermeability and adherens junction damage. Conclusions: VE‐cadherin disruption in animals results in hyperpermeability. Parallel studies in RLMEC demonstrated similar results. In addition, inhibition of proteasomal degradation attenuated microvascular hyperpermeability. These findings have significance in understanding the role of VE‐cadherin in regulating vascular hyperpermeability.
Url:
DOI: 10.1111/j.1549-8719.2010.00067.x
Affiliations:
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Sawant</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Surgery, Scott & White Memorial Hospital, Texas A&M University Health Science Center College of Medicine, Temple, Texas</wicri:regionArea><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Tharakan, Binu" sort="Tharakan, Binu" uniqKey="Tharakan B" first="Binu" last="Tharakan">Binu Tharakan</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Surgery, Scott & White Memorial Hospital, Texas A&M University Health Science Center College of Medicine, Temple, Texas</wicri:regionArea><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Adekanbi, Ashton" sort="Adekanbi, Ashton" uniqKey="Adekanbi A" first="Ashton" last="Adekanbi">Ashton Adekanbi</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Undergraduate Medical Academy, Prairie View A&M University, Prairie View, Texas</wicri:regionArea><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Hunter, Felicia A" sort="Hunter, Felicia A" uniqKey="Hunter F" first="Felicia A." last="Hunter">Felicia A. 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Childs</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Surgery, Scott & White Memorial Hospital, Texas A&M University Health Science Center College of Medicine, Temple, Texas</wicri:regionArea><placeName><region type="state">Texas</region></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Microcirculation</title><title level="j" type="alt">MICROCIRCULATION</title><idno type="ISSN">1073-9688</idno><idno type="eISSN">1549-8719</idno><imprint><biblScope unit="vol">18</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="46">46</biblScope><biblScope unit="page" to="55">55</biblScope><biblScope unit="page-count">10</biblScope><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2011-01">2011-01</date></imprint><idno type="ISSN">1073-9688</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1073-9688</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Adherens</term><term>Adherens junction</term><term>Adherens junctional</term><term>Adherens junctions</term><term>Binding sites</term><term>Blood volume</term><term>Blue color</term><term>Bronectin</term><term>Cadherin</term><term>Chloroquine</term><term>Chloroquine diphosphate</term><term>Competitive binding</term><term>Complete media</term><term>Control cells</term><term>Control group</term><term>Control monolayers</term><term>Control transit</term><term>Control values</term><term>Cytoplasmic</term><term>Cytoplasmic levels</term><term>Cytoskeletal</term><term>Cytoskeletal assembly</term><term>Dapi staining</term><term>Degradation</term><term>Endogenous</term><term>Endothelial</term><term>Endothelial cells</term><term>Extracellular</term><term>Extracellular domain</term><term>Extravasation</term><term>Extravascular space</term><term>Glass bottom dishes</term><term>Hyperpermeability</term><term>Immunoblot analysis</term><term>Inhibitor</term><term>John wiley sons</term><term>Junctional</term><term>Junctional damage</term><term>Luciferase</term><term>Luciferase activity</term><term>Luciferase reporter assay</term><term>Lung microvascular</term><term>Lysosomal</term><term>Lysosomal inhibitor</term><term>Mesenteric postcapillary venules</term><term>Microcirculation</term><term>Microvascular</term><term>Microvascular hyperpermeability</term><term>Monolayer</term><term>Monolayer hyperpermeability</term><term>Monolayer permeability</term><term>Monolayers</term><term>Mutant</term><term>Mutant protein</term><term>Optical intensity</term><term>Parallel studies</term><term>Pathway</term><term>Permeability</term><term>Physiol</term><term>Polyclonal antibody</term><term>Postcapillary</term><term>Proteasomal</term><term>Proteasomal degradation</term><term>Proteasomal inhibitor</term><term>Proteasome</term><term>Proteasome inhibitor</term><term>Protein levels</term><term>Reagent</term><term>Recombinant</term><term>Recombinant cytoplasmic domain</term><term>Rhodamine phalloidin</term><term>Room temperature</term><term>Santa cruz biotechnology</term><term>Sirna</term><term>Transcriptional</term><term>Transcriptional activation</term><term>Transcriptional activity</term><term>Transfected</term><term>Transfected cells</term><term>Transfected group</term><term>Transfection</term><term>Transfection reagent</term><term>Transwell plates</term><term>Untreated</term><term>Untreated control cells</term><term>Untreated control group</term><term>Untreated monolayers</term><term>Uorescent</term><term>Uorescent intensity</term><term>Uorometric plate reader</term><term>Vascular</term><term>Vascular hyperpermeability</term><term>Vascular permeability</term><term>Venule</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Please cite this paper as: Sawant, Tharakan, Adekanbi, Hunter, Smythe and Childs (2011). Inhibition of VE‐Cadherin Proteasomal Degradation Attenuates Microvascular Hyperpermeability. Microcirculation18(1), 46–55. Abstract: Objective: VE‐cadherin, an integral component of the adherens junction complex, is processed through the endosome–lysosome pathway and proteasome system for degradation. Our objective was to determine if inhibition of this pathway would protect against microvascular hyperpermeability. Methods: To induce VE‐cadherin degradation, we utilized a mutant VE‐cadherin protein that lacks the extracellular domain (rVE‐cad CPD). Intravital microscopy was employed to study the changes in microvascular permeability in rat mesenteric postcapillary venules. Rat lung microvascular endothelial cell (RLMEC) monolayers were utilized in parallel studies. The adherens junction integrity was determined using VE‐cadherin and β‐catenin immunofluorescence. TOPflash/FOPflash transfection and luciferase reporter assay were performed to study β‐catenin‐mediated transcriptional activation. Results: rVE‐cad CPD (2.5 μg/mL of blood volume) increased hyperpermeability significantly (p < 0.05). The VE‐cadherin siRNA as well as rVE‐cad CPD induced significant increase in monolayer hyperpermeability (p < 0.05). Transfection of rVE‐cad CPD disrupted adherens junctions evidenced by discontinuity in β‐catenin and VE‐cadherin immunofluorescence (p < 0.05). Proteasome inhibitor MG132 attenuated rVE‐cad CPD induced monolayer hyperpermeability and adherens junction damage. Conclusions: VE‐cadherin disruption in animals results in hyperpermeability. Parallel studies in RLMEC demonstrated similar results. In addition, inhibition of proteasomal degradation attenuated microvascular hyperpermeability. These findings have significance in understanding the role of VE‐cadherin in regulating vascular hyperpermeability.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Texas</li></region></list><tree><country name="États-Unis"><region name="Texas"><name sortKey="Sawant, Devendra A" sort="Sawant, Devendra A" uniqKey="Sawant D" first="Devendra A." last="Sawant">Devendra A. Sawant</name></region><name sortKey="Adekanbi, Ashton" sort="Adekanbi, Ashton" uniqKey="Adekanbi A" first="Ashton" last="Adekanbi">Ashton Adekanbi</name><name sortKey="Childs, Ed W" sort="Childs, Ed W" uniqKey="Childs E" first="Ed W." last="Childs">Ed W. Childs</name><name sortKey="Hunter, Felicia A" sort="Hunter, Felicia A" uniqKey="Hunter F" first="Felicia A." last="Hunter">Felicia A. Hunter</name><name sortKey="Smythe, William Roy" sort="Smythe, William Roy" uniqKey="Smythe W" first="William Roy" last="Smythe">William Roy Smythe</name><name sortKey="Tharakan, Binu" sort="Tharakan, Binu" uniqKey="Tharakan B" first="Binu" last="Tharakan">Binu Tharakan</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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