Assessment of the direct effects of DDAH I on tumour angiogenesis in vivo.
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Date
2018-11-01Author
Papaevangelou, E
Boult, JKR
Whitley, GS
Robinson, SP
Howe, FA
Type
Journal Article
Metadata
Show full item recordAbstract
Nitric oxide (NO) has been strongly implicated in glioma progression and angiogenesis. The endogenous inhibitors of NO synthesis, asymmetric dimethylarginine (ADMA) and N-monomethyl-L-arginine (L-NMMA), are metabolized by dimethylarginine dimethylaminohydrolase (DDAH), and hence, DDAH is an intracellular factor that regulates NO. However, DDAH may also have an NO-independent action. We aimed to investigate whether DDAH I has any direct role in tumour vascular development and growth independent of its NO-mediated effects, in order to establish the future potential of DDAH inhibition as an anti-angiogenic treatment strategy. A clone of rat C6 glioma cells deficient in NO production expressing a pTet Off regulatable element was identified and engineered to overexpress DDAH I in the absence of doxycycline. Xenografts derived from these cells were propagated in the presence or absence of doxycycline and susceptibility magnetic resonance imaging used to assess functional vasculature in vivo. Pathological correlates of tumour vascular density, maturation and function were also sought. In the absence of doxycycline, tumours exhibited high DDAH I expression and activity, which was suppressed in its presence. However, overexpression of DDAH I had no measurable effect on tumour growth, vessel density, function or maturation. These data suggest that in C6 gliomas DDAH has no NO-independent effects on tumour growth and angiogenesis, and that the therapeutic potential of targeting DDAH in gliomas should only be considered in the context of NO regulation.
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https://link.springer.com/content/pdf/10.1007/s10456-018-9617-6.pdfCollections
Subject
Cell Line, Tumor
Animals
Mice
Mice, Nude
Rats
Glioma
Neovascularization, Pathologic
Nitric Oxide
Amidohydrolases
Neoplasm Proteins
Neoplasm Transplantation
Female
Heterografts
Research team
Pre-Clinical MRI
Language
eng
Date accepted
2018-04-24
License start date
2018-11
Citation
Angiogenesis, 2018, 21 (4), pp. 737 - 749
Publisher
SPRINGER