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

• Published in: Pflügers Archiv 2015-09, Vol.467 (9), p.1945-1963
• Main Authors: Waeckel, Ludovic, Badier-Commander, Cécile, Damery, Thibaut, Köhler, Ralf, Sansilvestri-Morel, Patricia, Simonet, Serge, Vayssettes-Courchay, Christine, Wulff, Heike, Félétou, Michel
• Format: Article
• Language: English
• Subjects: Animals; Aorta - physiopathology; Aortic Aneurysm - physiopathology; Biomedical and Life Sciences; Biomedicine; Cell Biology; Disease Models, Animal; Endothelium, Vascular - physiopathology; Female; Human Physiology; Humans; Hypertension - complications; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular and Cellular Mechanisms of Disease; Molecular Medicine; Neurosciences; Organ Culture Techniques; Oxidative Stress - physiology; Polymerase Chain Reaction; Receptors; Vasodilation - physiology
• ISSN: 0031-6768; 1432-2013
• DOI: 10.1007/s00424-014-1644-6

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.