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

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.

In times of tobacco‐free nicotine consumption: The influence of nicotine on vascular calcification

“…In addition, MMP‐2 and ‐9 enzyme activity is activated upon nicotine treatment and the elastin architecture is disturbed in the aortic tissue compared to untreated control animals . The inhibition of MMP‐2 and ‐9 prevents nicotine‐induced aortic stiffening . The studies by Wagenhäuser et al and Hashimoto et al differ in the application route of nicotine and treatment period: 0.5 mg/mL nicotine solution diet over 14 days or 25 mg/kg/day nicotine infusion via micropump over 10 or 40 day, respectively .…”

“…The inhibition of MMP‐2 and ‐9 prevents nicotine‐induced aortic stiffening . The studies by Wagenhäuser et al and Hashimoto et al differ in the application route of nicotine and treatment period: 0.5 mg/mL nicotine solution diet over 14 days or 25 mg/kg/day nicotine infusion via micropump over 10 or 40 day, respectively . MMP‐2 and ‐9 activation upon nicotine could also be shown in vitro in human and rat VSMC …”

“…84 Nicotine infusion in mice increased PWV after 10 and 40 days of treatment. 85 In addition, MMP-2 85,86 and -9 85 enzyme activity is activated upon nicotine treatment and the elastin architecture is disturbed in the aortic tissue compared to untreated control animals. 85,86 The inhibition of MMP-2 and -9 prevents nicotine-induced aortic stiffening.…”

“…85 The studies by Wagenhäuser et al 85 and Hashimoto et al 86 differ in the application route of nicotine and treatment period: 0.5 mg/ mL nicotine solution diet over 14 days 86 or 25 mg/kg/day nicotine infusion via micropump over 10 or 40 day, respectively. 85 MMP-2 and -9 activation upon nicotine could also be shown in vitro in human and rat VSMC. [87][88][89] These data indicate that nicotine is able to promote mVC by facilitating extracellular matrix degradation (Figure 3).…”

“…Activation of NFkB-pathway and inflammatory mediators Inflammation Osteoblastic trans-differentiation 36,40,42,106 Reduced activity of eNOS Endothelial dysfunction Osteoblastic trans-differentiation 58,60 Lowering antioxidant defense Generation of ROS Osteoblastic trans-differentiation 67 Increased expression of MMP-2 and -9 Facilitated calciumphosphate deposition Extracellular matrix degradation [85][86][87][88][89] Increased calcium-influx in VSMC potentially leading to apoptosis and matrix vesicles Facilitated calciumphosphate deposition Formation of nucleation nidus 79…”