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Vascular dysfunctions in the isolated aorta of double-transgenic hypertensive mice developing aortic aneurysm

  • Molecular and cellular mechanisms of disease
  • Published:
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Abstract

Angiotensin-II and oxidative stress are involved in the genesis of aortic aneurysms, a phenomenon exacerbated by endothelial nitric oxide synthase (eNOS) deletion or uncoupling. The purpose of this work was to study the endothelial function in wild-type C57BL/6 (BL) and transgenic mice expressing the h-angiotensinogen and h-renin genes (AR) subjected to either a control, or a high-salt diet plus a treatment with a NO-synthase inhibitor, N-ω-nitro-l-arginine-methyl-ester (l-NAME; BLSL and ARSL). BLSL showed a moderate increase in blood pressure, while ARSL became severely hypertensive. Seventy-five percent of ARSL developed aortic aneurysms, characterized by major histo-morphological changes and associated with an increase in NADP(H) oxidase-2 (NOX2) expression. Contractile responses (KCl, norepinephrine, U-46619) were similar in the four groups of mice, and relaxations were not affected in BLSL and AR. However, in ARSL, endothelium-dependent relaxations (acetylcholine, UK-14304) were significantly reduced, and this dysfunction was similar in aortae without or with aneurysms. The endothelial impairment was unaffected by catalase, superoxide-dismutase mimetic, radical scavengers, cyclooxygenase inhibition, or TP-receptor blockade and could not be attributed to sGC oxidation. Thus, ARSL is a severe hypertension model developing aortic aneurysm. A vascular dysfunction, involving both endothelial (reduced role of NO) and smooth muscle cells, precedes aneurysms formation and, paradoxically, does not appear to involve oxidative stress.

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Acknowledgments

The authors are grateful to Catherine de Montrion, Monique Naze, and Jean-François Boivin for biochemical and histological analysis.

Conflict of interest

Ludovic Waeckel, Cécile Badier-Commander, Patricia Sansilvestri-Morel, Serge Simonet, Christine Vayssettes-Courchay, and Michel Félétou are, or were, employees of the Institut de Recherches Servier, a research institution belonging to the Groupe de Recherches Servier, a Pharmaceutical Company.

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Authors and Affiliations

  1. Institut de Recherches Servier, 92150, Suresnes, France

    Ludovic Waeckel, Cécile Badier-Commander, Thibaut Damery, Patricia Sansilvestri-Morel, Serge Simonet, Christine Vayssettes-Courchay & Michel Félétou

  2. Centre de Recherche des Cordeliers, Inserm UMRS 872, Paris, France

    Ludovic Waeckel & Christine Vayssettes-Courchay

  3. Cardiovascular and Renal Research, IMM, University of Southern and Denmark, Odense, Denmark

    Ralf Köhler & Christine Vayssettes-Courchay

  4. Aragon Institute of Health Sciences-I+CS and ARAID, Zaragoza, Spain

    Ralf Köhler & Christine Vayssettes-Courchay

  5. Department of Pharmacology, University of California, Davis, CA, 95616, USA

    Christine Vayssettes-Courchay & Heike Wulff

Authors
  1. Ludovic Waeckel
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  2. Cécile Badier-Commander
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  3. Thibaut Damery
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  4. Ralf Köhler
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  5. Patricia Sansilvestri-Morel
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  6. Serge Simonet
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  7. Christine Vayssettes-Courchay
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  8. Heike Wulff
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  9. Michel Félétou
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Corresponding author

Correspondence to Michel Félétou.

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Waeckel, L., Badier-Commander, C., Damery, T. et al. Vascular dysfunctions in the isolated aorta of double-transgenic hypertensive mice developing aortic aneurysm. Pflugers Arch - Eur J Physiol 467, 1945–1963 (2015). https://doi.org/10.1007/s00424-014-1644-6

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  • DOI: https://doi.org/10.1007/s00424-014-1644-6

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