Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL, USA.
Institute of Cardiovascular Disease, University of South China, Hengyang, China.
Physiol Rep. 2020 Nov;8(22):e14631. doi: 10.14814/phy2.14631.
Fewer females develop AADs (ascending aortic aneurysms and dissections) and the reasons for this protection remain poorly understood. The present study seeks to develop a mouse model that may be utilized to address this sexual dimorphism. Adult normolipidemic mice were challenged with BAPN (β-aminopropionitrile), AngII (angiotensin II), or BAPN + AngII. An initial protocol optimization found that 0.2% BAPN in drinking water plus AngII-infusion at 1,000 ng kg min produced favorable rates of AAD rupture (50%) and dilation (40%) in 28 days. Using these dosages, further experiments revealed that BAPN is toxic to naïve mature aortas and it acted synergistically with AngII to promote aortic tears and dissections. BAPN + AngII provoked early infiltration of myeloid cells and subsequent recruitment of lymphoid cells to the aortic wall. AADs established with BAPN + AngII, but not AngII alone, continued to expand after the cessation of AngII-infusion. This indefinite growth precipitated a 61% increase in the AAD diameter in 56 days. More importantly, with the optimized protocol, significant differences in AAD dilation (p = .012) and medial degeneration (p = .036) were detected between male and female mice. Treatment of ovariectomized mice with estradiol protected AAD formation (p = .014). In summary, this study developed a powerful mouse AAD model that can be used to study the sexual dimorphism in AAD formation.
女性较少发生 AAD（升主动脉瘤和夹层），其保护机制仍知之甚少。本研究旨在建立一种可能用于解决这种性别二态性的小鼠模型。成年正常血脂小鼠接受 BAPN（β-氨基丙腈）、AngII（血管紧张素 II）或 BAPN+AngII 挑战。最初的方案优化发现，在饮用水中添加 0.2%BAPN 并输注 AngII（1000ng/kg/min）可在 28 天内产生约 50%的 AAD 破裂率和约 40%的扩张率。使用这些剂量，进一步的实验表明 BAPN 对幼稚成熟主动脉有毒性，并且与 AngII 协同作用促进主动脉撕裂和夹层。BAPN+AngII 引发髓样细胞早期浸润，随后淋巴样细胞募集到主动脉壁。用 BAPN+AngII 建立的 AAD，而不是单独的 AngII，在 AngII 输注停止后继续扩张。这种无限期的生长导致 AAD 直径在 56 天内增加了 61%。更重要的是，使用优化方案，在 AAD 扩张（p=0.012）和中膜变性（p=0.036）方面，雄性和雌性小鼠之间存在显著差异。用雌二醇治疗去卵巢小鼠可预防 AAD 形成（p=0.014）。总之，本研究建立了一种强大的小鼠 AAD 模型，可用于研究 AAD 形成中的性别二态性。
