Tobacco
smoke is an established risk factor for
thoracic aortic aneurysms and dissections (
TAAD). However, little is known about its underlying mechanisms due to the lack of validated animal models. The present study developed a mouse model that may be utilized to investigate exacerbation of
TAAD formation by mimetics of tobacco
smoke. TAADs were created via inducible deletion of smooth muscle cell-specific
Tgfbr2 receptors. Using this model, the first set of experiments evaluated the efficacy of
nicotine salt (34.0 mg/kg/day),
nicotine free base (NFB, 5.0 mg 90-day pellets), and cigarette
smoke extract (0.1 ml/mouse/day). Compared with their respective control groups, only NFB pellets promoted
TAAD dilation (23 ± 3% vs. 12 ± 2%, P = 0.014), and this efficacy was achieved at a cost of >50% acute mortality. Infusion of NFB with osmotic minipumps at extremely high, but nonlethal, doses (15.0 or 45.0 mg/kg/day) failed to accelerate
TAAD dilation. Interestingly, costimulation with β-
aminopropionitrile (
BAPN) promoted
TAAD dilation and
aortic rupture at dosages of 3.0 and 45.0 mg/kg/day, respectively, indicating that
BAPN sensitizes the response of TAADs to NFB. In subsequent analyses, the detrimental effects of NFB were associated with clustering of macrophages, neutrophils, and T-cells in areas with structural destruction, enhanced
matrix metalloproteinase- (
MMP-) 2 production, and
pathological angiogenesis with attenuated
fibrosis in the adventitia. In conclusion, modeling
nicotine exacerbation of
TAAD formation requires optimization of chemical form, route of delivery, and dosage of the
drug as well as the pathologic complexity of TAADs. Under the optimized conditions of the present study, chronic
inflammation and adventitial mal-remodeling serve as critical pathways through which NFB exacerbates
TAAD formation.