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

Journal of Cell Science 120, 929-942 (2007)
Published by The Company of Biologists 2007
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Research Article

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

Beata Wojciak-Stothard1,*, Belen Torondel1, Lillian Yen Fen Tsang1, Ingrid Fleming2, Beate Fisslthaler2, James M. Leiper1 and Patrick Vallance1

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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© The Company of Biologists Ltd 2007