The ADMA/DDAH pathway regulates VEGF-mediated angiogenesis

Fiedler, L. R., Bachetti, T., Leiper, J. , Zachary, I., Chen, L., Renné, T. and Wojciak-Stothard, B. (2009) The ADMA/DDAH pathway regulates VEGF-mediated angiogenesis. Arteriosclerosis, Thrombosis, and Vascular Biology, 29(12), pp. 2117-2124. (doi:10.1161/ATVBAHA.109.194035) (PMID:19778944)

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Abstract

Objectives— Asymmetrical dimethylarginine (ADMA) is a nitric oxide synthase (NOS) inhibitor and cardiovascular risk factor associated with angiogenic disorders. Enzymes metabolising ADMA, dimethylarginine dimethylaminohydrolases (DDAH) promote angiogenesis, but the mechanisms are not clear. We hypothesized that ADMA/DDAH modifies endothelial responses to vascular endothelial growth factor (VEGF) by affecting activity of Rho GTPases, regulators of actin polymerization, and focal adhesion dynamics. Methods and Results— The effects of ADMA on VEGF-induced endothelial cell motility, focal adhesion turnover, and angiogenesis were studied in human umbilical vein endothelial cells (HUVECs) and DDAH I heterozygous knockout mice. ADMA inhibited VEGF-induced chemotaxis in vitro and angiogenesis in vitro and in vivo in an NO-dependent way. ADMA effects were prevented by overexpression of DDAH but were not associated with decreased proliferation, increased apoptosis, or changes in VEGFR-2 activity or expression. ADMA inhibited endothelial cell polarization, protrusion formation, and decreased focal adhesion dynamics, resulting from Rac1 inhibition after decrease in phosphorylation of vasodilator stimulated phosphoprotein (VASP). Constitutively active Rac1, and to a lesser extent dominant negative RhoA, abrogated ADMA effects in vitro and in vivo. Conclusion— The ADMA/DDAH pathway regulates VEGF-induced angiogenesis in an NO- and Rac1-dependent manner.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Leiper, Professor James
Authors: Fiedler, L. R., Bachetti, T., Leiper, J., Zachary, I., Chen, L., Renné, T., and Wojciak-Stothard, B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher:American Heart Association
ISSN:1079-5642
ISSN (Online):1524-4636
Published Online:18 November 2009

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