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Substrate stiffening promotes endothelial monolayer disruption through enhanced physical forces
A hallmark of many, sometimes life-threatening, inflammatory diseases and disorders is vascular leakage. The extent and severity of vascular leakage is broadly mediated by the integrity of the endothelial cell (EC) monolayer, which is in turn governed by three major interactions: cell-cell and cell-...
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Published in: | American Journal of Physiology: Cell Physiology 2011-01, Vol.300 (1), p.C146-C154 |
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creator | Krishnan, Ramaswamy Klumpers, Darinka D Park, Chan Y Rajendran, Kavitha Trepat, Xavier van Bezu, Jan van Hinsbergh, Victor W M Carman, Christopher V Brain, Joseph D Fredberg, Jeffrey J Butler, James P van Nieuw Amerongen, Geerten P |
description | A hallmark of many, sometimes life-threatening, inflammatory diseases and disorders is vascular leakage. The extent and severity of vascular leakage is broadly mediated by the integrity of the endothelial cell (EC) monolayer, which is in turn governed by three major interactions: cell-cell and cell-substrate contacts, soluble mediators, and biomechanical forces. A potentially critical but essentially uninvestigated component mediating these interactions is the stiffness of the substrate to which the endothelial monolayer is adherent. Accordingly, we investigated the extent to which substrate stiffening influences endothelial monolayer disruption and the role of cell-cell and cell-substrate contacts, soluble mediators, and physical forces in that process. Traction force microscopy showed that forces between cell and cell and between cell and substrate were greater on stiffer substrates. On stiffer substrates, these forces were substantially enhanced by a hyperpermeability stimulus (thrombin, 1 U/ml), and gaps formed between cells. On softer substrates, by contrast, these forces were increased far less by thrombin, and gaps did not form between cells. This stiffness-dependent force enhancement was associated with increased Rho kinase activity, whereas inhibition of Rho kinase attenuated baseline forces and lessened thrombin-induced inter-EC gap formation. Our findings demonstrate a central role of physical forces in EC gap formation and highlight a novel physiological mechanism. Integrity of the endothelial monolayer is governed by its physical microenvironment, which in normal circumstances is compliant but during pathology becomes stiffer. |
doi_str_mv | 10.1152/ajpcell.00195.2010 |
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The extent and severity of vascular leakage is broadly mediated by the integrity of the endothelial cell (EC) monolayer, which is in turn governed by three major interactions: cell-cell and cell-substrate contacts, soluble mediators, and biomechanical forces. A potentially critical but essentially uninvestigated component mediating these interactions is the stiffness of the substrate to which the endothelial monolayer is adherent. Accordingly, we investigated the extent to which substrate stiffening influences endothelial monolayer disruption and the role of cell-cell and cell-substrate contacts, soluble mediators, and physical forces in that process. Traction force microscopy showed that forces between cell and cell and between cell and substrate were greater on stiffer substrates. On stiffer substrates, these forces were substantially enhanced by a hyperpermeability stimulus (thrombin, 1 U/ml), and gaps formed between cells. On softer substrates, by contrast, these forces were increased far less by thrombin, and gaps did not form between cells. This stiffness-dependent force enhancement was associated with increased Rho kinase activity, whereas inhibition of Rho kinase attenuated baseline forces and lessened thrombin-induced inter-EC gap formation. Our findings demonstrate a central role of physical forces in EC gap formation and highlight a novel physiological mechanism. Integrity of the endothelial monolayer is governed by its physical microenvironment, which in normal circumstances is compliant but during pathology becomes stiffer.</description><identifier>ISSN: 0363-6143</identifier><identifier>EISSN: 1522-1563</identifier><identifier>DOI: 10.1152/ajpcell.00195.2010</identifier><identifier>PMID: 20861463</identifier><identifier>CODEN: AJPCDD</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Acrylic Resins ; Antigens, CD - metabolism ; Biochemistry ; Biomechanical Phenomena ; Biomechanics ; Cadherins - metabolism ; Cell Adhesion - drug effects ; Cell Adhesion - physiology ; Cells ; Cells, Cultured ; Cellular biology ; Culture Media - chemistry ; Endothelial Cells - cytology ; Endothelial Cells - drug effects ; Endothelial Cells - physiology ; Humans ; Kinases ; Membranes, Artificial ; Microscopy ; rho-Associated Kinases - metabolism ; Thrombin - pharmacology ; Vascular Biology</subject><ispartof>American Journal of Physiology: Cell Physiology, 2011-01, Vol.300 (1), p.C146-C154</ispartof><rights>Copyright American Physiological Society Jan 2011</rights><rights>Copyright © 2011 the American Physiological Society 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c494t-b0efd5f3ae29200c8f203edcd0c35c290a22732541114e29246f9a583b73a7013</citedby><cites>FETCH-LOGICAL-c494t-b0efd5f3ae29200c8f203edcd0c35c290a22732541114e29246f9a583b73a7013</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20861463$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Krishnan, Ramaswamy</creatorcontrib><creatorcontrib>Klumpers, Darinka D</creatorcontrib><creatorcontrib>Park, Chan Y</creatorcontrib><creatorcontrib>Rajendran, Kavitha</creatorcontrib><creatorcontrib>Trepat, Xavier</creatorcontrib><creatorcontrib>van Bezu, Jan</creatorcontrib><creatorcontrib>van Hinsbergh, Victor W M</creatorcontrib><creatorcontrib>Carman, Christopher V</creatorcontrib><creatorcontrib>Brain, Joseph D</creatorcontrib><creatorcontrib>Fredberg, Jeffrey J</creatorcontrib><creatorcontrib>Butler, James P</creatorcontrib><creatorcontrib>van Nieuw Amerongen, Geerten P</creatorcontrib><title>Substrate stiffening promotes endothelial monolayer disruption through enhanced physical forces</title><title>American Journal of Physiology: Cell Physiology</title><addtitle>Am J Physiol Cell Physiol</addtitle><description>A hallmark of many, sometimes life-threatening, inflammatory diseases and disorders is vascular leakage. The extent and severity of vascular leakage is broadly mediated by the integrity of the endothelial cell (EC) monolayer, which is in turn governed by three major interactions: cell-cell and cell-substrate contacts, soluble mediators, and biomechanical forces. A potentially critical but essentially uninvestigated component mediating these interactions is the stiffness of the substrate to which the endothelial monolayer is adherent. Accordingly, we investigated the extent to which substrate stiffening influences endothelial monolayer disruption and the role of cell-cell and cell-substrate contacts, soluble mediators, and physical forces in that process. Traction force microscopy showed that forces between cell and cell and between cell and substrate were greater on stiffer substrates. On stiffer substrates, these forces were substantially enhanced by a hyperpermeability stimulus (thrombin, 1 U/ml), and gaps formed between cells. On softer substrates, by contrast, these forces were increased far less by thrombin, and gaps did not form between cells. This stiffness-dependent force enhancement was associated with increased Rho kinase activity, whereas inhibition of Rho kinase attenuated baseline forces and lessened thrombin-induced inter-EC gap formation. Our findings demonstrate a central role of physical forces in EC gap formation and highlight a novel physiological mechanism. Integrity of the endothelial monolayer is governed by its physical microenvironment, which in normal circumstances is compliant but during pathology becomes stiffer.</description><subject>Acrylic Resins</subject><subject>Antigens, CD - metabolism</subject><subject>Biochemistry</subject><subject>Biomechanical Phenomena</subject><subject>Biomechanics</subject><subject>Cadherins - metabolism</subject><subject>Cell Adhesion - drug effects</subject><subject>Cell Adhesion - physiology</subject><subject>Cells</subject><subject>Cells, Cultured</subject><subject>Cellular biology</subject><subject>Culture Media - chemistry</subject><subject>Endothelial Cells - cytology</subject><subject>Endothelial Cells - drug effects</subject><subject>Endothelial Cells - physiology</subject><subject>Humans</subject><subject>Kinases</subject><subject>Membranes, Artificial</subject><subject>Microscopy</subject><subject>rho-Associated Kinases - metabolism</subject><subject>Thrombin - pharmacology</subject><subject>Vascular Biology</subject><issn>0363-6143</issn><issn>1522-1563</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><recordid>eNpVkU9LAzEQxYMotla_gAdZvG-dTHa33Ysg4j8QPKjnkGaTbso2WZOs0G9vaqvoKTDzey8z8wg5pzCltMQrseql6ropAK3LKQKFAzJODcxpWbFDMgZWsbyiBRuRkxBWAFBgVR-TEcI8lSs2Jvx1WIToRVRZiEZrZY1dZr13axdVyJRtXGxVZ0SXrZ11ndgonzUm-KGPxtkstt4NyzaBrbBSNVnfboKRCdfOSxVOyZEWXVBn-3dC3u_v3m4f8-eXh6fbm-dcFnUR8wUo3ZSaCYU1Asi5RmCqkQ1IVkqsQSDOGJYFpbTYMkWla1HO2WLGxAwom5DrnW8_LNZJqGxaquO9N2vhN9wJw_93rGn50n1yBshojcngcm_g3cegQuQrN3ibZuZzxLJKx6sShDtIeheCV_r3Awp8mwnfZ8K_M-HbTJLo4u9ov5KfENgXwzaMYw</recordid><startdate>20110101</startdate><enddate>20110101</enddate><creator>Krishnan, Ramaswamy</creator><creator>Klumpers, Darinka D</creator><creator>Park, Chan Y</creator><creator>Rajendran, Kavitha</creator><creator>Trepat, Xavier</creator><creator>van Bezu, Jan</creator><creator>van Hinsbergh, Victor W M</creator><creator>Carman, Christopher V</creator><creator>Brain, Joseph D</creator><creator>Fredberg, Jeffrey J</creator><creator>Butler, James P</creator><creator>van Nieuw Amerongen, Geerten P</creator><general>American Physiological Society</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>7QP</scope><scope>7TS</scope><scope>5PM</scope></search><sort><creationdate>20110101</creationdate><title>Substrate stiffening promotes endothelial monolayer disruption through enhanced physical forces</title><author>Krishnan, Ramaswamy ; Klumpers, Darinka D ; Park, Chan Y ; Rajendran, Kavitha ; Trepat, Xavier ; van Bezu, Jan ; van Hinsbergh, Victor W M ; Carman, Christopher V ; Brain, Joseph D ; Fredberg, Jeffrey J ; Butler, James P ; van Nieuw Amerongen, Geerten P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c494t-b0efd5f3ae29200c8f203edcd0c35c290a22732541114e29246f9a583b73a7013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Acrylic Resins</topic><topic>Antigens, CD - metabolism</topic><topic>Biochemistry</topic><topic>Biomechanical Phenomena</topic><topic>Biomechanics</topic><topic>Cadherins - metabolism</topic><topic>Cell Adhesion - drug effects</topic><topic>Cell Adhesion - physiology</topic><topic>Cells</topic><topic>Cells, Cultured</topic><topic>Cellular biology</topic><topic>Culture Media - chemistry</topic><topic>Endothelial Cells - cytology</topic><topic>Endothelial Cells - drug effects</topic><topic>Endothelial Cells - physiology</topic><topic>Humans</topic><topic>Kinases</topic><topic>Membranes, Artificial</topic><topic>Microscopy</topic><topic>rho-Associated Kinases - metabolism</topic><topic>Thrombin - pharmacology</topic><topic>Vascular Biology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Krishnan, Ramaswamy</creatorcontrib><creatorcontrib>Klumpers, Darinka D</creatorcontrib><creatorcontrib>Park, Chan Y</creatorcontrib><creatorcontrib>Rajendran, Kavitha</creatorcontrib><creatorcontrib>Trepat, Xavier</creatorcontrib><creatorcontrib>van Bezu, Jan</creatorcontrib><creatorcontrib>van Hinsbergh, Victor W M</creatorcontrib><creatorcontrib>Carman, Christopher V</creatorcontrib><creatorcontrib>Brain, Joseph D</creatorcontrib><creatorcontrib>Fredberg, Jeffrey J</creatorcontrib><creatorcontrib>Butler, James P</creatorcontrib><creatorcontrib>van Nieuw Amerongen, Geerten P</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Physical Education Index</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American Journal of Physiology: Cell Physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Krishnan, Ramaswamy</au><au>Klumpers, Darinka D</au><au>Park, Chan Y</au><au>Rajendran, Kavitha</au><au>Trepat, Xavier</au><au>van Bezu, Jan</au><au>van Hinsbergh, Victor W M</au><au>Carman, Christopher V</au><au>Brain, Joseph D</au><au>Fredberg, Jeffrey J</au><au>Butler, James P</au><au>van Nieuw Amerongen, Geerten P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Substrate stiffening promotes endothelial monolayer disruption through enhanced physical forces</atitle><jtitle>American Journal of Physiology: Cell Physiology</jtitle><addtitle>Am J Physiol Cell Physiol</addtitle><date>2011-01-01</date><risdate>2011</risdate><volume>300</volume><issue>1</issue><spage>C146</spage><epage>C154</epage><pages>C146-C154</pages><issn>0363-6143</issn><eissn>1522-1563</eissn><coden>AJPCDD</coden><notes>R. Krishnan and D. D. Klumpers contributed equally to this work.</notes><abstract>A hallmark of many, sometimes life-threatening, inflammatory diseases and disorders is vascular leakage. The extent and severity of vascular leakage is broadly mediated by the integrity of the endothelial cell (EC) monolayer, which is in turn governed by three major interactions: cell-cell and cell-substrate contacts, soluble mediators, and biomechanical forces. A potentially critical but essentially uninvestigated component mediating these interactions is the stiffness of the substrate to which the endothelial monolayer is adherent. Accordingly, we investigated the extent to which substrate stiffening influences endothelial monolayer disruption and the role of cell-cell and cell-substrate contacts, soluble mediators, and physical forces in that process. Traction force microscopy showed that forces between cell and cell and between cell and substrate were greater on stiffer substrates. On stiffer substrates, these forces were substantially enhanced by a hyperpermeability stimulus (thrombin, 1 U/ml), and gaps formed between cells. On softer substrates, by contrast, these forces were increased far less by thrombin, and gaps did not form between cells. This stiffness-dependent force enhancement was associated with increased Rho kinase activity, whereas inhibition of Rho kinase attenuated baseline forces and lessened thrombin-induced inter-EC gap formation. Our findings demonstrate a central role of physical forces in EC gap formation and highlight a novel physiological mechanism. Integrity of the endothelial monolayer is governed by its physical microenvironment, which in normal circumstances is compliant but during pathology becomes stiffer.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>20861463</pmid><doi>10.1152/ajpcell.00195.2010</doi><oa>free_for_read</oa></addata></record> |
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subjects | Acrylic Resins Antigens, CD - metabolism Biochemistry Biomechanical Phenomena Biomechanics Cadherins - metabolism Cell Adhesion - drug effects Cell Adhesion - physiology Cells Cells, Cultured Cellular biology Culture Media - chemistry Endothelial Cells - cytology Endothelial Cells - drug effects Endothelial Cells - physiology Humans Kinases Membranes, Artificial Microscopy rho-Associated Kinases - metabolism Thrombin - pharmacology Vascular Biology |
title | Substrate stiffening promotes endothelial monolayer disruption through enhanced physical forces |
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