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Updated: Jun 20, 2026
09:03
Modified In Vivo Matrix Gel Plug Assay for Angiogenesis Studies
Published on: June 30, 2023
The ADMA/DDAH pathway regulates VEGF-mediated angiogenesis
Lorna R Fiedler1, Tiziana Bachetti, James Leiper
1National Heart and Lung Institute, Faculty of Medicine, Imperial College London, UK.
Arteriosclerosis, Thrombosis, and Vascular Biology
|September 26, 2009
Summary
Asymmetrical dimethylarginine (ADMA) impairs blood vessel growth by inhibiting nitric oxide (NO) and Rac1 activity. The dimethylarginine dimethylaminohydrolase (DDAH) pathway is key to regulating this process.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Endothelial Cell Biology
Background:
- Asymmetrical dimethylarginine (ADMA) is a known inhibitor of nitric oxide synthase (NOS) and a cardiovascular risk factor linked to angiogenic disorders.
- Dimethylarginine dimethylaminohydrolases (DDAH) metabolize ADMA and are known to promote angiogenesis, but the precise mechanisms remain unclear.
Purpose of the Study:
- To investigate the hypothesis that ADMA and DDAH modify endothelial responses to vascular endothelial growth factor (VEGF).
- To determine the role of Rho GTPases, actin polymerization, and focal adhesion dynamics in mediating ADMA/DDAH effects on angiogenesis.
Main Methods:
- Studies were conducted using human umbilical vein endothelial cells (HUVECs) and DDAH I heterozygous knockout mice.
- Assessed the impact of ADMA on VEGF-induced endothelial cell motility, focal adhesion turnover, and angiogenesis in vitro and in vivo.
- Investigated the involvement of Rac1 and RhoA signaling pathways, including VASP phosphorylation.
Main Results:
- ADMA inhibited VEGF-induced chemotaxis and angiogenesis in a nitric oxide (NO)-dependent manner.
- ADMA's effects were reversed by DDAH overexpression and were independent of endothelial cell proliferation or apoptosis.
- ADMA impaired endothelial cell polarization and protrusion formation by inhibiting Rac1 activity, which was linked to decreased VASP phosphorylation.
Conclusions:
- The ADMA/DDAH pathway is a critical regulator of VEGF-induced angiogenesis.
- This regulation occurs in a manner dependent on both nitric oxide (NO) and the small GTPase Rac1.
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