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Front Physiol. 2018 Oct 31;9:1459. doi: 10.3389/fphys.2018.01459. eCollection 2018.

Chronic Nicotine Exposure Induces Murine Aortic Remodeling and Stiffness Segmentation-Implications for Abdominal Aortic Aneurysm Susceptibility.

Author information

1
Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States.
2
VA Palo Alto Health Care System, Palo Alto, CA, United States.
3
Department of Vascular and Endovascular Surgery, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
4
Molecular and Translational Vascular Medicine, Department of Cardiology and Pneumology, Heart Center at the University Medical Center Göttingen, Göttingen, Germany.
5
German Center for Cardiovascular Research e.V., Göttingen, Germany.
6
Department of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.
7
Department of Cardiac Surgery, University Hospital Munich, Ludwig-Maximilian-University, Munich, Germany.
8
Department of Surgery, University of California, San Francisco, San Francisco, CA, United States.
9
Department of Cardiology, Royal North Shore Hospital, The Kolling Institute, Northern Clinical School, University of Sydney, Sydney, NSW, Australia.
10
Department of Biomedical, Chemical and Materials Engineering, San Jose State University, San Jose, CA, United States.

Abstract

Aim: Arterial stiffness is a significant risk factor for many cardiovascular diseases, including abdominal aortic aneurysms (AAA). Nicotine, the major active ingredient of e-cigarettes and tobacco smoke, induces acute vasomotor effects that may temporarily increase arterial stiffness. Here, we investigated the effects of long-term nicotine exposure on structural aortic stiffness. Methods: Mice (C57BL/6) were infused with nicotine for 40 days (20 mg/kg/day). Arterial stiffness of the thoracic (TS) and abdominal (AS) aortic segments was analyzed using ultrasound (PWV, pulse wave velocity) and ex vivo pressure myograph measurements. For mechanistic studies, aortic matrix-metalloproteinase (MMP) expression and activity as well as medial elastin architecture were analyzed. Results: Global aortic stiffness increased with nicotine. In particular, local stiffening of the abdominal segment occurred after 10 days, while thoracic aortic stiffness was only increased after 40 days, resulting in aortic stiffness segmentation. Mechanistically, nicotine exposure enhanced expression of MMP-2/-9 and elastolytic activity in both aortic segments. Elastin degradation occurred in both segments; however, basal elastin levels were higher in the thoracic aorta. Finally, MMP-inhibition significantly reduced nicotine-induced MMP activity, elastin destruction, and aortic stiffening. Conclusion: Chronic nicotine exposure induces aortic MMP expression and structural aortic damage (elastin fragmentation), irreversibly increasing aortic stiffness. This process predominantly affects the abdominal aortic segment, presumably due in part to a lower basal elastin content. This novel phenomenon may help to explain the role of nicotine as a major risk factor for AAA formation and has health implications for ECIGs and other modes of nicotine delivery.

KEYWORDS:

AAA; e-cigarettes; mouse model; nicotine; segmentation; stiffness

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