Inhibition of VE-Cadherin Proteasomal Degradation Attenuates Microvascular Hyperpermeability
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. Objective: VE‐cadherin, an integral component of the adherens junction complex, is pro...
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| Veröffentlicht in: | Microcirculation (New York, N.Y. 1994) N.Y. 1994), 2011-01, Vol.18 (1), p.46-55 |
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| container_title | Microcirculation (New York, N.Y. 1994) |
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| creator | SAWANT, DEVENDRA A. THARAKAN, BINU ADEKANBI, ASHTON HUNTER, FELICIA A. SMYTHE, WILLIAM ROY CHILDS, ED W. |
| description | 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.
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 |
| doi_str_mv | 10.1111/j.1549-8719.2010.00067.x |
| format | Article |
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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.</description><identifier>ISSN: 1073-9688</identifier><identifier>EISSN: 1549-8719</identifier><identifier>DOI: 10.1111/j.1549-8719.2010.00067.x</identifier><identifier>PMID: 21166925</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Adherens junction ; Adherens Junctions - genetics ; Adherens Junctions - metabolism ; Animals ; Antigens, CD - genetics ; Antigens, CD - metabolism ; Cadherins - genetics ; Cadherins - metabolism ; Capillary Permeability - physiology ; Cells, Cultured ; Endothelial cells ; Endothelial Cells - metabolism ; Intravital microscopy ; Lung - blood supply ; Lung - metabolism ; Male ; Mutation ; Portal System - metabolism ; Proteasome Endopeptidase Complex - genetics ; Proteasome Endopeptidase Complex - metabolism ; Rats ; Rats, Sprague-Dawley ; Vascular hyperpermeability ; Venules - metabolism ; β-catenin</subject><ispartof>Microcirculation (New York, N.Y. 1994), 2011-01, Vol.18 (1), p.46-55</ispartof><rights>2010 John Wiley & Sons Ltd</rights><rights>2010 John Wiley & Sons Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4227-9e11fabba4042a8e0367d5d9e2fb875cf00354bc66171db0f66da21eaa1a833b3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1549-8719.2010.00067.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1549-8719.2010.00067.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21166925$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>SAWANT, DEVENDRA A.</creatorcontrib><creatorcontrib>THARAKAN, BINU</creatorcontrib><creatorcontrib>ADEKANBI, ASHTON</creatorcontrib><creatorcontrib>HUNTER, FELICIA A.</creatorcontrib><creatorcontrib>SMYTHE, WILLIAM ROY</creatorcontrib><creatorcontrib>CHILDS, ED W.</creatorcontrib><title>Inhibition of VE-Cadherin Proteasomal Degradation Attenuates Microvascular Hyperpermeability</title><title>Microcirculation (New York, N.Y. 1994)</title><addtitle>Microcirculation</addtitle><description>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.
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.</description><subject>Adherens junction</subject><subject>Adherens Junctions - genetics</subject><subject>Adherens Junctions - metabolism</subject><subject>Animals</subject><subject>Antigens, CD - genetics</subject><subject>Antigens, CD - metabolism</subject><subject>Cadherins - genetics</subject><subject>Cadherins - metabolism</subject><subject>Capillary Permeability - physiology</subject><subject>Cells, Cultured</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - metabolism</subject><subject>Intravital microscopy</subject><subject>Lung - blood supply</subject><subject>Lung - metabolism</subject><subject>Male</subject><subject>Mutation</subject><subject>Portal System - metabolism</subject><subject>Proteasome Endopeptidase Complex - genetics</subject><subject>Proteasome Endopeptidase Complex - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Vascular hyperpermeability</subject><subject>Venules - metabolism</subject><subject>β-catenin</subject><issn>1073-9688</issn><issn>1549-8719</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kMtu2zAQRYmiQfPqLxTadSWHpCSSArpJlDR2YOcB9LEpQAylUUNXD5eUEvvvQ8eJiQFI8J47i0NIxOiEhXO2nLAszWMlWT7hNPxSSoWcrD-Qo33wMbypTOJcKHVIjr1fBkgpnn8ih5wxIXKeHZE_s-7RGjvYvov6Ovp1FRdQPaKzXXTv-gHB9y000SX-dVDBK3Y-DNiNMKCPFrZ0_RP4cmzARdPNCl2YFsHYxg6bU3JQQ-Px89t9Qn5-v_pRTOP53fWsOJ_HZcq5jHNkrAZjIKUpB4U0EbLKqhx5bZTMyprSJEtNKQSTrDK0FqICzhCAgUoSk5yQr7u9K9f_H9EPurW-xKaBDvvRa8UZp5RlNJBf3sjRtFjplbMtuI1-FxKAbzvg2Ta42eeM6q14vdRbv3rrV2_F61fxeq0Xs6IQMtTjXd36Adf7Orh_OqQy079vr_Xt9OZCJJcX-iF5AVE6hrM</recordid><startdate>201101</startdate><enddate>201101</enddate><creator>SAWANT, DEVENDRA A.</creator><creator>THARAKAN, BINU</creator><creator>ADEKANBI, ASHTON</creator><creator>HUNTER, FELICIA A.</creator><creator>SMYTHE, WILLIAM ROY</creator><creator>CHILDS, ED W.</creator><general>Blackwell Publishing Ltd</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>201101</creationdate><title>Inhibition of VE-Cadherin Proteasomal Degradation Attenuates Microvascular Hyperpermeability</title><author>SAWANT, DEVENDRA A. ; THARAKAN, BINU ; ADEKANBI, ASHTON ; HUNTER, FELICIA A. ; SMYTHE, WILLIAM ROY ; CHILDS, ED W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4227-9e11fabba4042a8e0367d5d9e2fb875cf00354bc66171db0f66da21eaa1a833b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adherens junction</topic><topic>Adherens Junctions - genetics</topic><topic>Adherens Junctions - metabolism</topic><topic>Animals</topic><topic>Antigens, CD - genetics</topic><topic>Antigens, CD - metabolism</topic><topic>Cadherins - genetics</topic><topic>Cadherins - metabolism</topic><topic>Capillary Permeability - physiology</topic><topic>Cells, Cultured</topic><topic>Endothelial cells</topic><topic>Endothelial Cells - metabolism</topic><topic>Intravital microscopy</topic><topic>Lung - blood supply</topic><topic>Lung - metabolism</topic><topic>Male</topic><topic>Mutation</topic><topic>Portal System - metabolism</topic><topic>Proteasome Endopeptidase Complex - genetics</topic><topic>Proteasome Endopeptidase Complex - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Vascular hyperpermeability</topic><topic>Venules - metabolism</topic><topic>β-catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>SAWANT, DEVENDRA A.</creatorcontrib><creatorcontrib>THARAKAN, BINU</creatorcontrib><creatorcontrib>ADEKANBI, ASHTON</creatorcontrib><creatorcontrib>HUNTER, FELICIA A.</creatorcontrib><creatorcontrib>SMYTHE, WILLIAM ROY</creatorcontrib><creatorcontrib>CHILDS, ED W.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Microcirculation (New York, N.Y. 1994)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>SAWANT, DEVENDRA A.</au><au>THARAKAN, BINU</au><au>ADEKANBI, ASHTON</au><au>HUNTER, FELICIA A.</au><au>SMYTHE, WILLIAM ROY</au><au>CHILDS, ED W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of VE-Cadherin Proteasomal Degradation Attenuates Microvascular Hyperpermeability</atitle><jtitle>Microcirculation (New York, N.Y. 1994)</jtitle><addtitle>Microcirculation</addtitle><date>2011-01</date><risdate>2011</risdate><volume>18</volume><issue>1</issue><spage>46</spage><epage>55</epage><pages>46-55</pages><issn>1073-9688</issn><eissn>1549-8719</eissn><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.
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.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>21166925</pmid><doi>10.1111/j.1549-8719.2010.00067.x</doi><tpages>10</tpages></addata></record> |
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| subjects | Adherens junction Adherens Junctions - genetics Adherens Junctions - metabolism Animals Antigens, CD - genetics Antigens, CD - metabolism Cadherins - genetics Cadherins - metabolism Capillary Permeability - physiology Cells, Cultured Endothelial cells Endothelial Cells - metabolism Intravital microscopy Lung - blood supply Lung - metabolism Male Mutation Portal System - metabolism Proteasome Endopeptidase Complex - genetics Proteasome Endopeptidase Complex - metabolism Rats Rats, Sprague-Dawley Vascular hyperpermeability Venules - metabolism β-catenin |
| title | Inhibition of VE-Cadherin Proteasomal Degradation Attenuates Microvascular Hyperpermeability |
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