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First published online 27 February 2007
doi: 10.1242/jcs.002212

This Article Figures Only Full Text Full Text (PDF) Supplementary Material An erratum has been published All Versions of this Article: jcs.002212v1 120/6/929    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wojciak-Stothard, B. Articles by Vallance, P. Search for Related Content PubMed PubMed Citation Articles by Wojciak-Stothard, B. Articles by Vallance, P. Social Bookmarking                         What's this?

The ADMA/DDAH pathway is a critical regulator of endothelial cell motility

¹ BHF Laboratories, Department of Medicine, University College London, 5 University Street, London, WC1 E6JJ, UK
² Institut of Cardiovascular Physiology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany

^* Author for correspondence (e-mail: B.Wojciak-Stothard{at}ucl.ac.uk)

Accepted 15 January 2007

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.

Key words: Endothelial, Movement, Rho GTPases, Nitric oxide, Protein kinase G, Cytoskeleton

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