Inhibition of Rho kinases increases directional motility of microvascular endothelial cells
Rho kinases are major regulators of actin cytoskeletal organization and cell motility. Depending on the model system, inhibitors of Rho kinases (ROCK) have been reported to increase or decrease endothelial cell migration. In the present study we investigated the effect of Rho kinase inhibitors on mi...
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Veröffentlicht in: | Biochemical pharmacology 2012-03, Vol.83 (5), p.616-626 |
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description | Rho kinases are major regulators of actin cytoskeletal organization and cell motility. Depending on the model system, inhibitors of Rho kinases (ROCK) have been reported to increase or decrease endothelial cell migration. In the present study we investigated the effect of Rho kinase inhibitors on microvascular endothelial cell migration with a special focus on the isoform ROCK2.
Migration of microvascular endothelial cells was analyzed in a wound-healing, a spheroid-on-collagen migration assay and in cells embedded in collagen-1 gels. The non-selective Rho kinase inhibitor H1152 was compared to the selective ROCK2 inhibitor SLX2119 and to siRNA knock down.
Non-selective inhibition of Rho kinases decreased cell-spanning F-actin fibers, loosened cell–cell contacts visualized by VE cadherin staining, and reduced cell–matrix interactions as shown by reduced Hic-5 expression in focal contacts. Rho kinase inhibitors facilitated directed migration of endothelial cells away from spheroids on fibronectin-coated plates and in collagen-1 gels. By contrast, migration of firmly attached endothelial cells, resembling intact vessels, was not promoted by Rho kinase inhibition. Selective inhibition of ROCK2 mimicked the cytoskeletal effects of H1152 and also increased cell motility, although to a lesser extent.
In summary, Rho kinase inhibition enhanced the migration and cytoskeletal restructuring preferentially in freshly attached endothelial cells. ROCK2 may be a potential target to manipulate endothelial cell migration after vessel injury. |
doi_str_mv | 10.1016/j.bcp.2011.12.012 |
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Migration of microvascular endothelial cells was analyzed in a wound-healing, a spheroid-on-collagen migration assay and in cells embedded in collagen-1 gels. The non-selective Rho kinase inhibitor H1152 was compared to the selective ROCK2 inhibitor SLX2119 and to siRNA knock down.
Non-selective inhibition of Rho kinases decreased cell-spanning F-actin fibers, loosened cell–cell contacts visualized by VE cadherin staining, and reduced cell–matrix interactions as shown by reduced Hic-5 expression in focal contacts. Rho kinase inhibitors facilitated directed migration of endothelial cells away from spheroids on fibronectin-coated plates and in collagen-1 gels. By contrast, migration of firmly attached endothelial cells, resembling intact vessels, was not promoted by Rho kinase inhibition. Selective inhibition of ROCK2 mimicked the cytoskeletal effects of H1152 and also increased cell motility, although to a lesser extent.
In summary, Rho kinase inhibition enhanced the migration and cytoskeletal restructuring preferentially in freshly attached endothelial cells. ROCK2 may be a potential target to manipulate endothelial cell migration after vessel injury.</description><identifier>ISSN: 0006-2952</identifier><identifier>EISSN: 1873-2968</identifier><identifier>DOI: 10.1016/j.bcp.2011.12.012</identifier><identifier>PMID: 22192821</identifier><language>eng</language><publisher>England: Elsevier Inc</publisher><subject>1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives ; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology ; Actin cytoskeleton ; Animals ; Cell Adhesion ; Cell Line ; Cell motility ; Cell Movement - drug effects ; Collagen Type I - metabolism ; Connective tissue growth factor ; Endothelial Cells - drug effects ; Endothelial Cells - enzymology ; Mice ; Mice, Knockout ; Microvascular endothelial cells ; Rho kinase ; rho-Associated Kinases - antagonists & inhibitors ; rho-Associated Kinases - genetics ; rho-Associated Kinases - metabolism ; RNA Interference ; ROCK2 ; Tubulin - metabolism ; Vinculin - metabolism</subject><ispartof>Biochemical pharmacology, 2012-03, Vol.83 (5), p.616-626</ispartof><rights>2011 Elsevier Inc.</rights><rights>Copyright © 2011 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c352t-a271a49c9d48c50d1d9272f3984b8dfcb18b8f1f31412f67cc29f0db48ac7eb03</citedby><cites>FETCH-LOGICAL-c352t-a271a49c9d48c50d1d9272f3984b8dfcb18b8f1f31412f67cc29f0db48ac7eb03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bcp.2011.12.012$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22192821$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Breyer, Johannes</creatorcontrib><creatorcontrib>Samarin, Jana</creatorcontrib><creatorcontrib>Rehm, Margot</creatorcontrib><creatorcontrib>Lautscham, Lena</creatorcontrib><creatorcontrib>Fabry, Ben</creatorcontrib><creatorcontrib>Goppelt-Struebe, Margarete</creatorcontrib><title>Inhibition of Rho kinases increases directional motility of microvascular endothelial cells</title><title>Biochemical pharmacology</title><addtitle>Biochem Pharmacol</addtitle><description>Rho kinases are major regulators of actin cytoskeletal organization and cell motility. Depending on the model system, inhibitors of Rho kinases (ROCK) have been reported to increase or decrease endothelial cell migration. In the present study we investigated the effect of Rho kinase inhibitors on microvascular endothelial cell migration with a special focus on the isoform ROCK2.
Migration of microvascular endothelial cells was analyzed in a wound-healing, a spheroid-on-collagen migration assay and in cells embedded in collagen-1 gels. The non-selective Rho kinase inhibitor H1152 was compared to the selective ROCK2 inhibitor SLX2119 and to siRNA knock down.
Non-selective inhibition of Rho kinases decreased cell-spanning F-actin fibers, loosened cell–cell contacts visualized by VE cadherin staining, and reduced cell–matrix interactions as shown by reduced Hic-5 expression in focal contacts. Rho kinase inhibitors facilitated directed migration of endothelial cells away from spheroids on fibronectin-coated plates and in collagen-1 gels. By contrast, migration of firmly attached endothelial cells, resembling intact vessels, was not promoted by Rho kinase inhibition. Selective inhibition of ROCK2 mimicked the cytoskeletal effects of H1152 and also increased cell motility, although to a lesser extent.
In summary, Rho kinase inhibition enhanced the migration and cytoskeletal restructuring preferentially in freshly attached endothelial cells. ROCK2 may be a potential target to manipulate endothelial cell migration after vessel injury.</description><subject>1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives</subject><subject>1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology</subject><subject>Actin cytoskeleton</subject><subject>Animals</subject><subject>Cell Adhesion</subject><subject>Cell Line</subject><subject>Cell motility</subject><subject>Cell Movement - drug effects</subject><subject>Collagen Type I - metabolism</subject><subject>Connective tissue growth factor</subject><subject>Endothelial Cells - drug effects</subject><subject>Endothelial Cells - enzymology</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Microvascular endothelial cells</subject><subject>Rho kinase</subject><subject>rho-Associated Kinases - antagonists & inhibitors</subject><subject>rho-Associated Kinases - genetics</subject><subject>rho-Associated Kinases - metabolism</subject><subject>RNA Interference</subject><subject>ROCK2</subject><subject>Tubulin - metabolism</subject><subject>Vinculin - metabolism</subject><issn>0006-2952</issn><issn>1873-2968</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1Lw0AQhhdRbK3-AC-Sm6fGnUmabPAkxS8oCKInD8tmP-jWJFt300L_vRtbPXqaGXjmZeYh5BJoChSKm1Vay3WKFCAFTCngERkDK7MpVgU7JmNKaRH7GY7IWQirYWQFnJIRIlTIEMbk47lb2tr21nWJM8nr0iWfthNBh8R20uufTlmv5YCIJmldbxvb7wa6tdK7rQhy0wif6E65fqkbGympmyackxMjmqAvDnVC3h_u3-ZP08XL4_P8bjGV2Qz7qcASRF7JSuVMzqgCVWGJJqtYXjNlZA2sZgZMBjmgKUopsTJU1TkTstQ1zSbkep-79u5ro0PPWxuGC0Sn3SbwCspZycocIwl7Mt4dgteGr71thd9xoHxQylc8KuWDUg7Io9K4c3VI39StVn8bvw4jcLsHdPxxa7XnQVrdSb3XxpWz_8R_AzBwiF4</recordid><startdate>20120301</startdate><enddate>20120301</enddate><creator>Breyer, Johannes</creator><creator>Samarin, Jana</creator><creator>Rehm, Margot</creator><creator>Lautscham, Lena</creator><creator>Fabry, Ben</creator><creator>Goppelt-Struebe, Margarete</creator><general>Elsevier Inc</general><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>20120301</creationdate><title>Inhibition of Rho kinases increases directional motility of microvascular endothelial cells</title><author>Breyer, Johannes ; Samarin, Jana ; Rehm, Margot ; Lautscham, Lena ; Fabry, Ben ; Goppelt-Struebe, Margarete</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c352t-a271a49c9d48c50d1d9272f3984b8dfcb18b8f1f31412f67cc29f0db48ac7eb03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives</topic><topic>1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology</topic><topic>Actin cytoskeleton</topic><topic>Animals</topic><topic>Cell Adhesion</topic><topic>Cell Line</topic><topic>Cell motility</topic><topic>Cell Movement - drug effects</topic><topic>Collagen Type I - metabolism</topic><topic>Connective tissue growth factor</topic><topic>Endothelial Cells - drug effects</topic><topic>Endothelial Cells - enzymology</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Microvascular endothelial cells</topic><topic>Rho kinase</topic><topic>rho-Associated Kinases - antagonists & inhibitors</topic><topic>rho-Associated Kinases - genetics</topic><topic>rho-Associated Kinases - metabolism</topic><topic>RNA Interference</topic><topic>ROCK2</topic><topic>Tubulin - metabolism</topic><topic>Vinculin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Breyer, Johannes</creatorcontrib><creatorcontrib>Samarin, Jana</creatorcontrib><creatorcontrib>Rehm, Margot</creatorcontrib><creatorcontrib>Lautscham, Lena</creatorcontrib><creatorcontrib>Fabry, Ben</creatorcontrib><creatorcontrib>Goppelt-Struebe, Margarete</creatorcontrib><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>Biochemical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Breyer, Johannes</au><au>Samarin, Jana</au><au>Rehm, Margot</au><au>Lautscham, Lena</au><au>Fabry, Ben</au><au>Goppelt-Struebe, Margarete</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of Rho kinases increases directional motility of microvascular endothelial cells</atitle><jtitle>Biochemical pharmacology</jtitle><addtitle>Biochem Pharmacol</addtitle><date>2012-03-01</date><risdate>2012</risdate><volume>83</volume><issue>5</issue><spage>616</spage><epage>626</epage><pages>616-626</pages><issn>0006-2952</issn><eissn>1873-2968</eissn><abstract>Rho kinases are major regulators of actin cytoskeletal organization and cell motility. Depending on the model system, inhibitors of Rho kinases (ROCK) have been reported to increase or decrease endothelial cell migration. In the present study we investigated the effect of Rho kinase inhibitors on microvascular endothelial cell migration with a special focus on the isoform ROCK2.
Migration of microvascular endothelial cells was analyzed in a wound-healing, a spheroid-on-collagen migration assay and in cells embedded in collagen-1 gels. The non-selective Rho kinase inhibitor H1152 was compared to the selective ROCK2 inhibitor SLX2119 and to siRNA knock down.
Non-selective inhibition of Rho kinases decreased cell-spanning F-actin fibers, loosened cell–cell contacts visualized by VE cadherin staining, and reduced cell–matrix interactions as shown by reduced Hic-5 expression in focal contacts. Rho kinase inhibitors facilitated directed migration of endothelial cells away from spheroids on fibronectin-coated plates and in collagen-1 gels. By contrast, migration of firmly attached endothelial cells, resembling intact vessels, was not promoted by Rho kinase inhibition. Selective inhibition of ROCK2 mimicked the cytoskeletal effects of H1152 and also increased cell motility, although to a lesser extent.
In summary, Rho kinase inhibition enhanced the migration and cytoskeletal restructuring preferentially in freshly attached endothelial cells. ROCK2 may be a potential target to manipulate endothelial cell migration after vessel injury.</abstract><cop>England</cop><pub>Elsevier Inc</pub><pmid>22192821</pmid><doi>10.1016/j.bcp.2011.12.012</doi><tpages>11</tpages></addata></record> |
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subjects | 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology Actin cytoskeleton Animals Cell Adhesion Cell Line Cell motility Cell Movement - drug effects Collagen Type I - metabolism Connective tissue growth factor Endothelial Cells - drug effects Endothelial Cells - enzymology Mice Mice, Knockout Microvascular endothelial cells Rho kinase rho-Associated Kinases - antagonists & inhibitors rho-Associated Kinases - genetics rho-Associated Kinases - metabolism RNA Interference ROCK2 Tubulin - metabolism Vinculin - metabolism |
title | Inhibition of Rho kinases increases directional motility of microvascular endothelial cells |
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