P732Maternal high-fat diet promotes the expansion of abdominal aortic aneurysm in adult offspring by enhancing osteoclast-like macrophage differentiation

Abstract

Abstract Background and objective Maternal high-fat diet (HFD) has been shown to modulate vascular function and remodeling in adult offspring. Here, we investigated the impact of maternal HFD on abdominal aortic aneurysm (AAA) formation. Methods and results Eight-week-old female wild-type mice (C57BL/6) were fed a HFD or normal diet (ND) one week prior to mating and received during pregnancy and lactation. In eight-week-old offspring of both genders, AAA was induced with the application of 0.5M calcium chloride (CaCl2) on the infrarenal aorta. Male offspring of HFD-fed dams (O-HFD) showed a significant increase in maximum outer diameter of AAA at 1, 4 and 8 weeks after surgery compared with offspring of ND-fed dams (O-ND) (P<0.05). The lengths of outer circumference assessed by histological analysis were increased in O-HFD (P<0.05). Likewise, female O-HFD showed a greater length of outer circumference than female O-ND (P<0.05). While the number of F4/80-positive cells at 1 wk after surgery was comparable between the male O-HFD and O-ND, the percentage of MMP-9/F4/80 double-positive cells was significantly increased in male O-HFD. Consistently, fluorescent image of abdominal aorta taken by IVIS at 1 wk after surgery revealed a 2-fold increase in MMP activity (P<0.01). Intriguingly, F4/80-positive cells in male O-HFD showed a 2.5-fold increase in co-staining with tartrate-resistant acid phosphate (TRAP), typical marker of osteoclast-like macrophages which abundantly secrete proteases than classically activated macrophages (M1), while the percentage of TNF-α/F4/80 double-positive cells was comparable between the 2 groups. Pharmacological inhibition of osteoclastogenesis by zoledronic acid (ZA) (100μg/kg) completely abolished the exaggerated AAA development in male O-HFD to a similar extent of that in male O-ND, while AAA development in male O-ND mice did not change even after ZA treatment. Furthermore, in vitro TNF-α-induced osteoclast differentiation of bone marrow-derived macrophages (BMDMs) showed a significantly higher number of TRAP-positive cells, accompanied by increased calcitonin receptor mRNA expression. Western blotting analysis showed that protein expression level of NFATc1, master regulator of osteoclastogenesis, was significantly higher in BMDM of O-HFD than O-ND. Conclusion Our findings demonstrate that maternal HFD accelerates CaCl2-induced AAA expansion, accompanied by the exaggerated accumulation of osteoclast-like macrophages and augmented activity of MMPs. Inhibition of macrophages skewing toward osteoclast-like cells could be a potential therapeutic target for preventing AAA development.