The ADMA/DDAH pathway regulates VEGF-mediated angiogenesis

Lorna R. Fiedler, Tiziana Bachetti, James Leiper, Ian Zachary, Lihua Chen, Thomas Renné, Beata Wojciak-Stothard

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2117-2124
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume29
Issue number12
DOIs
Publication statusPublished - Dec 2009

Keywords

  • ADMA
  • Angiogenesis
  • DDAH I
  • Rho GTPase
  • VEGF

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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