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Assessment of the direct effects of DDAH I on tumour angiogenesis in vivo

Papaevangelou, E; Boult, JKR; Whitley, GS; Robinson, SP; Howe, FA (2018) Assessment of the direct effects of DDAH I on tumour angiogenesis in vivo. ANGIOGENESIS, 21 (4). pp. 737-749. ISSN 0969-6970 https://doi.org/10.1007/s10456-018-9617-6
SGUL Authors: Whitley, Guy St John

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Abstract

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.

Item Type: Article
Additional Information: © The Author(s) 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Keywords: Oncology & Carcinogenesis, 1103 Clinical Sciences, 1115 Pharmacology And Pharmaceutical Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: ANGIOGENESIS
ISSN: 0969-6970
Dates:
DateEvent
November 2018Published
2 May 2018Published Online
24 April 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
G0700019Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G0800110Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
09-0310Association for International Cancer Researchhttp://dx.doi.org/10.13039/501100000391
S20430Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
URI: https://openaccess.sgul.ac.uk/id/eprint/109783
Publisher's version: https://doi.org/10.1007/s10456-018-9617-6

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