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

Wojciak-Stothard, B., Torondel, B., Tsang, L. Y. F., Fleming, I., Fisslthaler, B., Leiper, J. M. and Vallance, P. (2007) The ADMA/DDAH pathway is a critical regulator of endothelial cell motility. Journal of Cell Science, 120(6), pp. 929-942. (doi:10.1242/jcs.002212) (PMID:17327280)

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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. 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Leiper, Professor James
Authors: Wojciak-Stothard, B., Torondel, B., Tsang, L. Y. F., Fleming, I., Fisslthaler, B., Leiper, J. M., and Vallance, P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of Cell Science
ISSN:0021-9533
ISSN (Online):1477-9137
Published Online:27 February 2007

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