Cyclic AMP and Acidic Fibroblast Growth Factor Have Opposing Effects on Tight and Adherens Junctions in Microvascular Endothelial Cells in Vitro
Endothelial adherens junctions (AJ) and tight junctions (TJ) are important determinants of vascular permeability and cell morphology. Here, we investigate their regulation, in primary human placental microvascular endothelial cell (HPMEC) cultures, by either aFGF plus heparin (ECGS) or elevated cAMP...
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description | Endothelial adherens junctions (AJ) and tight junctions (TJ) are important determinants of vascular permeability and cell morphology. Here, we investigate their regulation, in primary human placental microvascular endothelial cell (HPMEC) cultures, by either aFGF plus heparin (ECGS) or elevated cAMP. The proliferation of HPMEC was weakly stimulated by ECGS, while cAMP was inhibitory. ECGS had little effect on transendothelial resistance (TER), but increased macromolecular permeability, whereas cAMP induced a twofold increase in TER and reduced macromolecular permeability. Ultrastructurally, ECGS-treated HPMEC exhibited an “activated” phenotype typified by proliferating cells, with poorly organized cell–cell junctions, whereas cAMP-treated cells appeared quiescent and markedly flattened with extended paracellular junctions, resembling endothelium in situ. The expression and localization of junctional molecules, F-actin, and junctional phosphotyrosine were examined by confocal microscopy and immunoblotting. Junctional molecules in ECGS-treated cells were less organized at lateral membranes than in control cells, whereas in cAMP-treated cells, they were highly localized at continuous contacts. These differences correlated with the intensity of junctional phosphotyrosine, being lowest with cAMP treatment. In the AJ of ECGS-treated and control cells, β-catenin predominated but in cAMP-treated cells, γ-catenin/plakoglobin was enriched. In addition, cAMP upregulated junctional expression of VE-cadherin and PECAM-1 and increased the levels of the TJ molecules occludin and ZO−1. The expression levels of junctional components, and their tyrosine phosphorylation, play an important role in dynamic regulation of endothelial cell–cell junctions. |
doi_str_mv | 10.1006/mvre.2001.2333 |
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Here, we investigate their regulation, in primary human placental microvascular endothelial cell (HPMEC) cultures, by either aFGF plus heparin (ECGS) or elevated cAMP. The proliferation of HPMEC was weakly stimulated by ECGS, while cAMP was inhibitory. ECGS had little effect on transendothelial resistance (TER), but increased macromolecular permeability, whereas cAMP induced a twofold increase in TER and reduced macromolecular permeability. Ultrastructurally, ECGS-treated HPMEC exhibited an “activated” phenotype typified by proliferating cells, with poorly organized cell–cell junctions, whereas cAMP-treated cells appeared quiescent and markedly flattened with extended paracellular junctions, resembling endothelium in situ. The expression and localization of junctional molecules, F-actin, and junctional phosphotyrosine were examined by confocal microscopy and immunoblotting. Junctional molecules in ECGS-treated cells were less organized at lateral membranes than in control cells, whereas in cAMP-treated cells, they were highly localized at continuous contacts. These differences correlated with the intensity of junctional phosphotyrosine, being lowest with cAMP treatment. In the AJ of ECGS-treated and control cells, β-catenin predominated but in cAMP-treated cells, γ-catenin/plakoglobin was enriched. In addition, cAMP upregulated junctional expression of VE-cadherin and PECAM-1 and increased the levels of the TJ molecules occludin and ZO−1. The expression levels of junctional components, and their tyrosine phosphorylation, play an important role in dynamic regulation of endothelial cell–cell junctions.</description><identifier>ISSN: 0026-2862</identifier><identifier>EISSN: 1095-9319</identifier><identifier>DOI: 10.1006/mvre.2001.2333</identifier><identifier>PMID: 11516239</identifier><identifier>CODEN: MIVRA6</identifier><language>eng</language><publisher>Amsterdam: Elsevier Inc</publisher><subject>Actins - metabolism ; adherens junction ; Adherens Junctions - drug effects ; Adherens Junctions - metabolism ; Adherens Junctions - ultrastructure ; Biological and medical sciences ; Cadherins - metabolism ; Capillary Permeability ; Cell Adhesion - physiology ; Cell Division - drug effects ; Cell Division - physiology ; Cell Size - drug effects ; Cell Surface Extensions - metabolism ; Cell Surface Extensions - ultrastructure ; Cells, Cultured ; confocal microscopy ; Culture Media, Serum-Free ; Cyclic AMP - pharmacology ; Cytoskeletal Proteins - metabolism ; Electric Impedance ; electron microscopy ; Embryology: invertebrates and vertebrates. Teratology ; endothelial permeability ; Endothelium, Vascular - drug effects ; Endothelium, Vascular - metabolism ; Endothelium, Vascular - ultrastructure ; Female ; Fetal membranes ; Fibroblast Growth Factor 1 - pharmacology ; Fundamental and applied biological sciences. Psychology ; General aspects. Development. Fetal membranes ; Humans ; Membrane Proteins - metabolism ; Microcirculation ; Microscopy, Fluorescence ; Occludin ; Phosphoproteins - metabolism ; Placenta - blood supply ; Placenta - cytology ; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism ; Pregnancy ; tight junction ; Tight Junctions - drug effects ; Tight Junctions - metabolism ; Tight Junctions - ultrastructure ; VE-cadherin ; Zonula Occludens-1 Protein</subject><ispartof>Microvascular research, 2001-09, Vol.62 (2), p.94-113</ispartof><rights>2001 Academic Press</rights><rights>2002 INIST-CNRS</rights><rights>Copyright 2001 Academic Press.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c370t-a16a18b150a7dd1f814c50efc26365d51f3574b4f9961fc2ec73ae03290524c43</citedby><cites>FETCH-LOGICAL-c370t-a16a18b150a7dd1f814c50efc26365d51f3574b4f9961fc2ec73ae03290524c43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1006/mvre.2001.2333$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14061773$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11516239$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dye, Julian F.</creatorcontrib><creatorcontrib>Leach, Lopa</creatorcontrib><creatorcontrib>Clark, Peter</creatorcontrib><creatorcontrib>Firth, J.Anthony</creatorcontrib><title>Cyclic AMP and Acidic Fibroblast Growth Factor Have Opposing Effects on Tight and Adherens Junctions in Microvascular Endothelial Cells in Vitro</title><title>Microvascular research</title><addtitle>Microvasc Res</addtitle><description>Endothelial adherens junctions (AJ) and tight junctions (TJ) are important determinants of vascular permeability and cell morphology. Here, we investigate their regulation, in primary human placental microvascular endothelial cell (HPMEC) cultures, by either aFGF plus heparin (ECGS) or elevated cAMP. The proliferation of HPMEC was weakly stimulated by ECGS, while cAMP was inhibitory. ECGS had little effect on transendothelial resistance (TER), but increased macromolecular permeability, whereas cAMP induced a twofold increase in TER and reduced macromolecular permeability. Ultrastructurally, ECGS-treated HPMEC exhibited an “activated” phenotype typified by proliferating cells, with poorly organized cell–cell junctions, whereas cAMP-treated cells appeared quiescent and markedly flattened with extended paracellular junctions, resembling endothelium in situ. The expression and localization of junctional molecules, F-actin, and junctional phosphotyrosine were examined by confocal microscopy and immunoblotting. Junctional molecules in ECGS-treated cells were less organized at lateral membranes than in control cells, whereas in cAMP-treated cells, they were highly localized at continuous contacts. These differences correlated with the intensity of junctional phosphotyrosine, being lowest with cAMP treatment. In the AJ of ECGS-treated and control cells, β-catenin predominated but in cAMP-treated cells, γ-catenin/plakoglobin was enriched. In addition, cAMP upregulated junctional expression of VE-cadherin and PECAM-1 and increased the levels of the TJ molecules occludin and ZO−1. The expression levels of junctional components, and their tyrosine phosphorylation, play an important role in dynamic regulation of endothelial cell–cell junctions.</description><subject>Actins - metabolism</subject><subject>adherens junction</subject><subject>Adherens Junctions - drug effects</subject><subject>Adherens Junctions - metabolism</subject><subject>Adherens Junctions - ultrastructure</subject><subject>Biological and medical sciences</subject><subject>Cadherins - metabolism</subject><subject>Capillary Permeability</subject><subject>Cell Adhesion - physiology</subject><subject>Cell Division - drug effects</subject><subject>Cell Division - physiology</subject><subject>Cell Size - drug effects</subject><subject>Cell Surface Extensions - metabolism</subject><subject>Cell Surface Extensions - ultrastructure</subject><subject>Cells, Cultured</subject><subject>confocal microscopy</subject><subject>Culture Media, Serum-Free</subject><subject>Cyclic AMP - pharmacology</subject><subject>Cytoskeletal Proteins - metabolism</subject><subject>Electric Impedance</subject><subject>electron microscopy</subject><subject>Embryology: invertebrates and vertebrates. Teratology</subject><subject>endothelial permeability</subject><subject>Endothelium, Vascular - drug effects</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Endothelium, Vascular - ultrastructure</subject><subject>Female</subject><subject>Fetal membranes</subject><subject>Fibroblast Growth Factor 1 - pharmacology</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>General aspects. Development. Fetal membranes</subject><subject>Humans</subject><subject>Membrane Proteins - metabolism</subject><subject>Microcirculation</subject><subject>Microscopy, Fluorescence</subject><subject>Occludin</subject><subject>Phosphoproteins - metabolism</subject><subject>Placenta - blood supply</subject><subject>Placenta - cytology</subject><subject>Platelet Endothelial Cell Adhesion Molecule-1 - metabolism</subject><subject>Pregnancy</subject><subject>tight junction</subject><subject>Tight Junctions - drug effects</subject><subject>Tight Junctions - metabolism</subject><subject>Tight Junctions - ultrastructure</subject><subject>VE-cadherin</subject><subject>Zonula Occludens-1 Protein</subject><issn>0026-2862</issn><issn>1095-9319</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kTtvGzEQhIkgQSw7aVMGbJLuFC55D10pCJIfsGEXdlqCR-5ZDE6kQvIU-F_kJ4cXCXDlarnEt4PBDCFfgM2BsfrH7hBwzhmDORdCvCMzYG1VtALa92TGGK8Lvqj5GTmP8VemoGr5R3KWJ9RctDPyd_WiB6vp8u6BKmfoUluT143tgu8GFRO9DP5P2tKN0skHeqUOSO_3ex-te6brvkedIvWOPtrnbTpKmC0GdJHejE4n6_PLOnpndfAHFfU4qEDXzvi0xcGqga5wGP4jP20K_hP50Ksh4ufTvCBPm_Xj6qq4vb-8Xi1vCy0algoFtYJFBxVTjTHQL6DUFcNe81rUlamgF1VTdmXftjXkX9SNUMgEb1nFS12KC_L9qLsP_veIMcmdjTpbUQ79GGUDAFywKoPzI5j9xxiwl_tgdyq8SGBy6kBOHcipAzl1kA--npTHbofmFT-FnoFvJyDHoYY-KKdtfOVKVkPTTEKLI4c5h4PFIKO26DQaG3Ls0nj7lod_Iu2jJA</recordid><startdate>20010901</startdate><enddate>20010901</enddate><creator>Dye, Julian F.</creator><creator>Leach, Lopa</creator><creator>Clark, Peter</creator><creator>Firth, J.Anthony</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20010901</creationdate><title>Cyclic AMP and Acidic Fibroblast Growth Factor Have Opposing Effects on Tight and Adherens Junctions in Microvascular Endothelial Cells in Vitro</title><author>Dye, Julian F. ; Leach, Lopa ; Clark, Peter ; Firth, J.Anthony</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c370t-a16a18b150a7dd1f814c50efc26365d51f3574b4f9961fc2ec73ae03290524c43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Actins - metabolism</topic><topic>adherens junction</topic><topic>Adherens Junctions - drug effects</topic><topic>Adherens Junctions - metabolism</topic><topic>Adherens Junctions - ultrastructure</topic><topic>Biological and medical sciences</topic><topic>Cadherins - metabolism</topic><topic>Capillary Permeability</topic><topic>Cell Adhesion - physiology</topic><topic>Cell Division - drug effects</topic><topic>Cell Division - physiology</topic><topic>Cell Size - drug effects</topic><topic>Cell Surface Extensions - metabolism</topic><topic>Cell Surface Extensions - ultrastructure</topic><topic>Cells, Cultured</topic><topic>confocal microscopy</topic><topic>Culture Media, Serum-Free</topic><topic>Cyclic AMP - pharmacology</topic><topic>Cytoskeletal Proteins - metabolism</topic><topic>Electric Impedance</topic><topic>electron microscopy</topic><topic>Embryology: invertebrates and vertebrates. Teratology</topic><topic>endothelial permeability</topic><topic>Endothelium, Vascular - drug effects</topic><topic>Endothelium, Vascular - metabolism</topic><topic>Endothelium, Vascular - ultrastructure</topic><topic>Female</topic><topic>Fetal membranes</topic><topic>Fibroblast Growth Factor 1 - pharmacology</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>General aspects. Development. Fetal membranes</topic><topic>Humans</topic><topic>Membrane Proteins - metabolism</topic><topic>Microcirculation</topic><topic>Microscopy, Fluorescence</topic><topic>Occludin</topic><topic>Phosphoproteins - metabolism</topic><topic>Placenta - blood supply</topic><topic>Placenta - cytology</topic><topic>Platelet Endothelial Cell Adhesion Molecule-1 - metabolism</topic><topic>Pregnancy</topic><topic>tight junction</topic><topic>Tight Junctions - drug effects</topic><topic>Tight Junctions - metabolism</topic><topic>Tight Junctions - ultrastructure</topic><topic>VE-cadherin</topic><topic>Zonula Occludens-1 Protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dye, Julian F.</creatorcontrib><creatorcontrib>Leach, Lopa</creatorcontrib><creatorcontrib>Clark, Peter</creatorcontrib><creatorcontrib>Firth, J.Anthony</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Microvascular research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dye, Julian F.</au><au>Leach, Lopa</au><au>Clark, Peter</au><au>Firth, J.Anthony</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cyclic AMP and Acidic Fibroblast Growth Factor Have Opposing Effects on Tight and Adherens Junctions in Microvascular Endothelial Cells in Vitro</atitle><jtitle>Microvascular research</jtitle><addtitle>Microvasc Res</addtitle><date>2001-09-01</date><risdate>2001</risdate><volume>62</volume><issue>2</issue><spage>94</spage><epage>113</epage><pages>94-113</pages><issn>0026-2862</issn><eissn>1095-9319</eissn><coden>MIVRA6</coden><abstract>Endothelial adherens junctions (AJ) and tight junctions (TJ) are important determinants of vascular permeability and cell morphology. Here, we investigate their regulation, in primary human placental microvascular endothelial cell (HPMEC) cultures, by either aFGF plus heparin (ECGS) or elevated cAMP. The proliferation of HPMEC was weakly stimulated by ECGS, while cAMP was inhibitory. ECGS had little effect on transendothelial resistance (TER), but increased macromolecular permeability, whereas cAMP induced a twofold increase in TER and reduced macromolecular permeability. Ultrastructurally, ECGS-treated HPMEC exhibited an “activated” phenotype typified by proliferating cells, with poorly organized cell–cell junctions, whereas cAMP-treated cells appeared quiescent and markedly flattened with extended paracellular junctions, resembling endothelium in situ. The expression and localization of junctional molecules, F-actin, and junctional phosphotyrosine were examined by confocal microscopy and immunoblotting. Junctional molecules in ECGS-treated cells were less organized at lateral membranes than in control cells, whereas in cAMP-treated cells, they were highly localized at continuous contacts. These differences correlated with the intensity of junctional phosphotyrosine, being lowest with cAMP treatment. In the AJ of ECGS-treated and control cells, β-catenin predominated but in cAMP-treated cells, γ-catenin/plakoglobin was enriched. In addition, cAMP upregulated junctional expression of VE-cadherin and PECAM-1 and increased the levels of the TJ molecules occludin and ZO−1. The expression levels of junctional components, and their tyrosine phosphorylation, play an important role in dynamic regulation of endothelial cell–cell junctions.</abstract><cop>Amsterdam</cop><pub>Elsevier Inc</pub><pmid>11516239</pmid><doi>10.1006/mvre.2001.2333</doi><tpages>20</tpages></addata></record> |
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subjects | Actins - metabolism adherens junction Adherens Junctions - drug effects Adherens Junctions - metabolism Adherens Junctions - ultrastructure Biological and medical sciences Cadherins - metabolism Capillary Permeability Cell Adhesion - physiology Cell Division - drug effects Cell Division - physiology Cell Size - drug effects Cell Surface Extensions - metabolism Cell Surface Extensions - ultrastructure Cells, Cultured confocal microscopy Culture Media, Serum-Free Cyclic AMP - pharmacology Cytoskeletal Proteins - metabolism Electric Impedance electron microscopy Embryology: invertebrates and vertebrates. Teratology endothelial permeability Endothelium, Vascular - drug effects Endothelium, Vascular - metabolism Endothelium, Vascular - ultrastructure Female Fetal membranes Fibroblast Growth Factor 1 - pharmacology Fundamental and applied biological sciences. Psychology General aspects. Development. Fetal membranes Humans Membrane Proteins - metabolism Microcirculation Microscopy, Fluorescence Occludin Phosphoproteins - metabolism Placenta - blood supply Placenta - cytology Platelet Endothelial Cell Adhesion Molecule-1 - metabolism Pregnancy tight junction Tight Junctions - drug effects Tight Junctions - metabolism Tight Junctions - ultrastructure VE-cadherin Zonula Occludens-1 Protein |
title | Cyclic AMP and Acidic Fibroblast Growth Factor Have Opposing Effects on Tight and Adherens Junctions in Microvascular Endothelial Cells in Vitro |
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