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Molecules 2017, 22(4), 627; doi:10.3390/molecules22040627

Pro-Angiogenic Effects of Low Dose Ethoxidine in a Murine Model of Ischemic Hindlimb: Correlation between Ethoxidine Levels and Increased Activation of the Nitric Oxide Pathway

1
MINT, Univ Angers, INSERM, CNRS, Université Bretagne Loire, IBS-CHU, 4 rue Larrey, F-49933 Angers, France
2
Department of Pharmaceutical Pharmacology and Physiology, UFR Santé-School of Pharmacy, University of Angers, F-49045 Angers, France
3
Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA
4
EA 2160, Univ Nantes, Université Bretagne Loire, F-44200 Nantes, France
5
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, CH-1211 Geneva 4, Switzerland
6
SONAS, SFR QUASAV 4207, UPRES EA921, Univ Angers, Université Bretagne Loire, F-49035 Angers, France
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Diego Muñoz-Torrero
Received: 3 March 2017 / Revised: 3 April 2017 / Accepted: 6 April 2017 / Published: 12 April 2017
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Abstract

Ethoxidine, a benzo[c]phenanthridine derivative, has been identified as a potent inhibitor of topoisomerase I in cancer cell lines. Our group has reported paradoxical properties of ethoxidine in cellular processes leading to angiogenesis on endothelial cells. Because low concentration ethoxidine is able to favor angiogenesis, the present study aimed to investigate the ability of 10−9 M ethoxidine to modulate neovascularization in a model of mouse hindlimb ischemia. After inducing unilateral hindlimb ischemia, mice were treated for 21 days with glucose 5% or with ethoxidine, to reach plasma concentrations equivalent to 10–9 M. Laser Doppler analysis showed that recovery of blood flow was 1.5 fold higher in ethoxidine-treated mice in comparison with control mice. Furthermore, CD31 staining and angiographic studies confirmed an increase of vascular density in ethoxidine-treated mice. This ethoxidine-induced recovery was associated with an increase of NO production through an enhancement of eNOS phosphorylation on its activator site in skeletal muscle from ischemic hindlimb. Moreover, real-time RT-PCR and western blots have highlighted that ethoxidine has pro-angiogenic properties by inducing a significant enhancement in vegf transcripts and VEGF expression, respectively. These findings suggest that ethoxidine could contribute to favor neovascularization after an ischemic injury by promoting the NO pathway and VEGF expression. View Full-Text
Keywords: ischemia; ethoxidine; nitric oxide; VEGF; angiogenesis; neovascularization ischemia; ethoxidine; nitric oxide; VEGF; angiogenesis; neovascularization
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MDPI and ACS Style

Clere, N.; To, K.H.T.; Legeay, S.; Bertrand, S.; Helesbeux, J.J.; Duval, O.; Faure, S. Pro-Angiogenic Effects of Low Dose Ethoxidine in a Murine Model of Ischemic Hindlimb: Correlation between Ethoxidine Levels and Increased Activation of the Nitric Oxide Pathway. Molecules 2017, 22, 627.

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