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A validated mouse model capable of recapitulating the protective effects of female sex hormones on ascending aortic aneurysms and dissections (AADs).

ABSTRACT: 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 (?-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^-1 min^-1 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.

SUBMITTER: Qi X

PROVIDER: S-EPMC7690909 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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A validated mouse model capable of recapitulating the protective effects of female sex hormones on ascending aortic aneurysms and dissections (AADs).

Qi Xiaoyan X Wang Fen F Chun Changzoon C Saldarriaga Lennon L Jiang Zhisheng Z Pruitt Eric Y EY Arnaoutakis George J GJ Upchurch Gilbert R GR Jiang Zhihua Z

Physiological reports 20201101 22

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<sup>-1</sup> min<sup>-1</sup> produc ...[more]

PMID: 33242364

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Project description:Pathological impairment of elastic fiber and other extracellular matrix (ECM) components are described for the aortic media of ascending thoracic aortic aneurysms (aTAA) but the exact pathological impairment of the structure and its degree still needs further investigations. To evaluate the quantity and quality of elastic fiber sheets and other ECM structures (e.g. collagen), cells were removed from different types of aneurysmal tissues (tricuspid aortic valve [TAV] associated-, bicuspid aortic valve [BAV] associated-aneurysmal tissue and acute aortic dissections [AAD]) using 2.5% sodium hydroxide (NaOH) and compared to decellularized control aortic tissue. Likewise, native tissue has been analysed. To evaluate the 2D- (histological evaluation, fluorescence- and auto-fluorescence based staining methods) and the 3D structure (scanning electron microscopic [SEM] examination) of the medial layer we first analysed for a successful decellularization. After proving for successful decellularization, we quantified the amount of elastic fiber sheets, elastin and other ECM components including collagen. Aside from clearly visible focal elastic fiber loss in TAV-aTAA tissue, decellularization resulted in reduction of elastic fiber auto-fluorescence properties, which is perhaps an indication from a disease-related qualitative impairment of elastic fibers, visible only after contact with the alkaline solution. Likewise, the loss of collagen amount in BAV-aTAA and TAV-aTAA tissue (compared to non-decellularized tissue) after contact with NaOH indicates a prior disease-associated impairment of collagen. Although the amount of ECM was not changed in type A dissection tissue, detailed electron microscopic evaluation revealed changes in ECM quality, which worsened after contact with alkaline solution but were not visible after histological analyses. Apart from the improved observation of the samples using electron microscopy, contact of aneurysmal and dissected tissue with the alkaline decellularization solution revealed potential disease related changes in ECM quality which can partly be connected to already published data, but have to be proven by further studies.

Dataset Information

A validated mouse model capable of recapitulating the protective effects of female sex hormones on ascending aortic aneurysms and dissections (AADs).

Publications

A validated mouse model capable of recapitulating the protective effects of female sex hormones on ascending aortic aneurysms and dissections (AADs).

Similar Datasets

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