ADMA/DDAH pathway is a critical regulator of endothelial cell motility
Asymmetric dimethylarginine (ADMA) is an inhibitor of nitric oxide production associated with abnormal blood vessel growth and repair, however, the mechanism of action of ADMA is not well understood. We studied the role of exogenous and endogenous ADMA in the regulation of cell motility and actin cy...
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| Veröffentlicht in: | Journal of cell science 2007-03, Vol.120 (6), p.929-942 |
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| creator | Wojciak-Stothard, Beata Torondel, Belen Tsang, Lillian Yen Fen Fleming, Ingrid Fisslthaler, Beate Leiper, James M Vallance, Patrick |
| description | Asymmetric dimethylarginine (ADMA) is an inhibitor of nitric oxide production associated with abnormal blood vessel growth and repair, however, the mechanism of action of ADMA is not well understood. We studied the role of exogenous and endogenous ADMA in the regulation of cell motility and actin cytoskeleton in porcine pulmonary endothelial cells (PAECs) and pulmonary microvascular endothelial cells (PMECs) from knockout mice that lack one of the enzyme metabolising ADMA, dimethylarginine dimethylaminohydrolase I (DDAHI) as well as endothelial cells overexpressing DDAH in vitro. We show that ADMA induced stress fibre and focal adhesion formation and inhibited cell motility in primary pulmonary endothelial cells. The effects of ADMA depended on the activity of RhoA and Rho kinase and were reversed by overexpression of DDAH, nitric oxide donors and protein kinase G activator, 8-bromo-cGMP. ADMA also inhibited the activities of Rac1 and Cdc42 in cells but these changes had a minor effect on cell motility. Endogenous ADMA increased RhoA activity and inhibited cell motility in PMECs from DDAHI knockout mice and inhibited angiogenesis in vitro. These results are the first demonstration that metabolism of cardiovascular risk factor ADMA regulates endothelial cell motility, an important factor in angiogenesis and vascular repair. |
| doi_str_mv | 10.1242/jcs.002212 |
| format | Article |
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We studied the role of exogenous and endogenous ADMA in the regulation of cell motility and actin cytoskeleton in porcine pulmonary endothelial cells (PAECs) and pulmonary microvascular endothelial cells (PMECs) from knockout mice that lack one of the enzyme metabolising ADMA, dimethylarginine dimethylaminohydrolase I (DDAHI) as well as endothelial cells overexpressing DDAH in vitro. We show that ADMA induced stress fibre and focal adhesion formation and inhibited cell motility in primary pulmonary endothelial cells. The effects of ADMA depended on the activity of RhoA and Rho kinase and were reversed by overexpression of DDAH, nitric oxide donors and protein kinase G activator, 8-bromo-cGMP. ADMA also inhibited the activities of Rac1 and Cdc42 in cells but these changes had a minor effect on cell motility. Endogenous ADMA increased RhoA activity and inhibited cell motility in PMECs from DDAHI knockout mice and inhibited angiogenesis in vitro. 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These results are the first demonstration that metabolism of cardiovascular risk factor ADMA regulates endothelial cell motility, an important factor in angiogenesis and vascular repair.</description><subject>Actin Cytoskeleton - drug effects</subject><subject>Actin Cytoskeleton - physiology</subject><subject>Amidohydrolases - genetics</subject><subject>Amidohydrolases - metabolism</subject><subject>Animals</subject><subject>Arginine - analogs & derivatives</subject><subject>Arginine - pharmacology</subject><subject>Arginine - physiology</subject><subject>cdc42 GTP-Binding Protein - metabolism</subject><subject>Cell Movement - drug effects</subject><subject>Cell Movement - physiology</subject><subject>Cells, Cultured</subject><subject>Cyclic GMP - analogs & derivatives</subject><subject>Cyclic GMP - pharmacology</subject><subject>Cyclic GMP-Dependent Protein Kinases - metabolism</subject><subject>Cytoskeleton - drug effects</subject><subject>Cytoskeleton - physiology</subject><subject>Endothelial Cells - drug effects</subject><subject>Endothelial Cells - physiology</subject><subject>Enzyme Activation</subject><subject>Focal Adhesions - physiology</subject><subject>Lung - blood supply</subject><subject>Lung - cytology</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Neovascularization, Physiologic - drug effects</subject><subject>rac1 GTP-Binding Protein - metabolism</subject><subject>rhoA GTP-Binding Protein - metabolism</subject><subject>rhoB GTP-Binding Protein - metabolism</subject><subject>Signal Transduction</subject><subject>Stress Fibers - physiology</subject><subject>Swine</subject><issn>0021-9533</issn><issn>1477-9137</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1LwzAch4Mobk4vfgDtyYPQLS9N0x7H5pww8aA7hzRNtox2mUmK7Nub0YFHT4F_Hn48PADcIzhGOMOTnfRjCDFG-AIMUcZYWiLCLsEwHlFaUkIG4Mb7HYSQ4ZJdgwFiBDNcwCFYTOfv08l8Pl0mBxG2P-KYGJ-IRDoTjBRN4tSma0SwLrE6Ufvahq1qTPyQqmmS1gbTmHC8BVdaNF7dnd8RWC9evmbLdPXx-jabrlKZIRRSJpEoqGIyy_NaZjXKSR6Fs4KUUFBBEMmxqupcM6HLSsi6iqKFpiLK5jXVZASe-t2Ds9-d8oG3xp9MxF7ZznMGcZzG2b8gKmkZK-EIPvegdNZ7pzQ_ONMKd-QI8lNeHvPyPm-EH86rXdWq-g8994zAYw9oYbnYOOP5-hNDRGJ6SiGh5Be1Lnz0</recordid><startdate>20070315</startdate><enddate>20070315</enddate><creator>Wojciak-Stothard, Beata</creator><creator>Torondel, Belen</creator><creator>Tsang, Lillian Yen Fen</creator><creator>Fleming, Ingrid</creator><creator>Fisslthaler, Beate</creator><creator>Leiper, James M</creator><creator>Vallance, Patrick</creator><general>The Company of Biologists Limited</general><scope>FBQ</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>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20070315</creationdate><title>ADMA/DDAH pathway is a critical regulator of endothelial cell motility</title><author>Wojciak-Stothard, Beata ; Torondel, Belen ; Tsang, Lillian Yen Fen ; Fleming, Ingrid ; Fisslthaler, Beate ; Leiper, James M ; Vallance, Patrick</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c411t-7c1a85e7c466dc4d163614748390a5a31362ebd6f7af9bacdb7328f5a7286d5f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Actin Cytoskeleton - drug effects</topic><topic>Actin Cytoskeleton - physiology</topic><topic>Amidohydrolases - genetics</topic><topic>Amidohydrolases - metabolism</topic><topic>Animals</topic><topic>Arginine - analogs & derivatives</topic><topic>Arginine - pharmacology</topic><topic>Arginine - physiology</topic><topic>cdc42 GTP-Binding Protein - metabolism</topic><topic>Cell Movement - drug effects</topic><topic>Cell Movement - physiology</topic><topic>Cells, Cultured</topic><topic>Cyclic GMP - analogs & derivatives</topic><topic>Cyclic GMP - pharmacology</topic><topic>Cyclic GMP-Dependent Protein Kinases - metabolism</topic><topic>Cytoskeleton - drug effects</topic><topic>Cytoskeleton - physiology</topic><topic>Endothelial Cells - drug effects</topic><topic>Endothelial Cells - physiology</topic><topic>Enzyme Activation</topic><topic>Focal Adhesions - physiology</topic><topic>Lung - blood supply</topic><topic>Lung - cytology</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Neovascularization, Physiologic - drug effects</topic><topic>rac1 GTP-Binding Protein - metabolism</topic><topic>rhoA GTP-Binding Protein - metabolism</topic><topic>rhoB GTP-Binding Protein - metabolism</topic><topic>Signal Transduction</topic><topic>Stress Fibers - physiology</topic><topic>Swine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wojciak-Stothard, Beata</creatorcontrib><creatorcontrib>Torondel, Belen</creatorcontrib><creatorcontrib>Tsang, Lillian Yen Fen</creatorcontrib><creatorcontrib>Fleming, Ingrid</creatorcontrib><creatorcontrib>Fisslthaler, Beate</creatorcontrib><creatorcontrib>Leiper, James M</creatorcontrib><creatorcontrib>Vallance, Patrick</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of cell science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wojciak-Stothard, Beata</au><au>Torondel, Belen</au><au>Tsang, Lillian Yen Fen</au><au>Fleming, Ingrid</au><au>Fisslthaler, Beate</au><au>Leiper, James M</au><au>Vallance, Patrick</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ADMA/DDAH pathway is a critical regulator of endothelial cell motility</atitle><jtitle>Journal of cell science</jtitle><addtitle>J Cell Sci</addtitle><date>2007-03-15</date><risdate>2007</risdate><volume>120</volume><issue>6</issue><spage>929</spage><epage>942</epage><pages>929-942</pages><issn>0021-9533</issn><eissn>1477-9137</eissn><abstract>Asymmetric dimethylarginine (ADMA) is an inhibitor of nitric oxide production associated with abnormal blood vessel growth and repair, however, the mechanism of action of ADMA is not well understood. We studied the role of exogenous and endogenous ADMA in the regulation of cell motility and actin cytoskeleton in porcine pulmonary endothelial cells (PAECs) and pulmonary microvascular endothelial cells (PMECs) from knockout mice that lack one of the enzyme metabolising ADMA, dimethylarginine dimethylaminohydrolase I (DDAHI) as well as endothelial cells overexpressing DDAH in vitro. We show that ADMA induced stress fibre and focal adhesion formation and inhibited cell motility in primary pulmonary endothelial cells. The effects of ADMA depended on the activity of RhoA and Rho kinase and were reversed by overexpression of DDAH, nitric oxide donors and protein kinase G activator, 8-bromo-cGMP. ADMA also inhibited the activities of Rac1 and Cdc42 in cells but these changes had a minor effect on cell motility. Endogenous ADMA increased RhoA activity and inhibited cell motility in PMECs from DDAHI knockout mice and inhibited angiogenesis in vitro. 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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Company of Biologists |
| subjects | Actin Cytoskeleton - drug effects Actin Cytoskeleton - physiology Amidohydrolases - genetics Amidohydrolases - metabolism Animals Arginine - analogs & derivatives Arginine - pharmacology Arginine - physiology cdc42 GTP-Binding Protein - metabolism Cell Movement - drug effects Cell Movement - physiology Cells, Cultured Cyclic GMP - analogs & derivatives Cyclic GMP - pharmacology Cyclic GMP-Dependent Protein Kinases - metabolism Cytoskeleton - drug effects Cytoskeleton - physiology Endothelial Cells - drug effects Endothelial Cells - physiology Enzyme Activation Focal Adhesions - physiology Lung - blood supply Lung - cytology Mice Mice, Knockout Neovascularization, Physiologic - drug effects rac1 GTP-Binding Protein - metabolism rhoA GTP-Binding Protein - metabolism rhoB GTP-Binding Protein - metabolism Signal Transduction Stress Fibers - physiology Swine |
| title | ADMA/DDAH pathway is a critical regulator of endothelial cell motility |
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