Dissecting abdominal aortic aneurysm in Ang II-infused mice: suprarenal branch ruptures and apparent luminal dilatation

Trachet, Bram; Fraga‐Silva, Rodrigo A.; Piersigilli, Alessandra; Tedgui, Alain; Sordet-Dessimoz, Jessica; Astolfo, Alberto; Donckt, Carole Van der; Modregger, Peter; Stampanoni, Marco; Segers, Patrick; Stergiopulos, Nikolaos

doi:10.1093/cvr/cvu257

Cited by 67 publications

(83 citation statements)

References 40 publications

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“…These findings are consistent with findings in human AD 18. Continued aortic stress activates proliferative and inflammatory responses, and these responses occur in parallel with the development of focal medial disruption to the aorta 15. We found that in WT mice, focal medial disruption of the aorta seldom led to the development of AD.…”

Section: Discussionsupporting

confidence: 91%

“…At 1 week after starting Ca+AngII treatment, most of the WT and mSocs3‐KO mice developed no AD. However, closer observation revealed a slight thickening of the aortic wall at the branching point of the celiac trunk or the superior mesenteric artery (Figure 1A and 1B; Video S1), as reported previously 15, 17. Histological examination showed that the thickened portion of the aorta contained cellular infiltration and fibrosis.…”

Section: Resultssupporting

confidence: 83%

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Role of Macrophage Socs3 in the Pathogenesis of Aortic Dissection

Ohno‐Urabe

Aoki

Nishihara

et al. 2018

JAHA

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BackgroundAortic dissection (AD) is a life‐threatening medical emergency caused by the abrupt destruction of the intimomedial layer of the aortic walls. Given that previous studies have reported the involvement of proinflammatory cytokine interleukin‐6 in AD pathogenesis, we investigated the role of signal transduction and activator of transcription 3 signaling, a downstream pathway of interleukin‐6 in macrophages in pathogenesis of AD.Methods and ResultsWe characterized the pathological and molecular events triggered by aortic stress, which can lead to AD. Aortic stress on the suprarenal aorta because of infrarenal aorta stiffening and angiotensin II infusion for 1 week caused focal medial rupture at the branching point of the celiac trunk and superior mesenteric artery. This focal medial rupture healed in 6 weeks in wild‐type (WT) mice, but progressed to AD in mice with macrophage‐specific deletion of Socs3 gene (mSocs3‐KO). mSocs3‐KO mice showed premature activation of cell proliferation, an inflammatory response, and skewed differentiation of macrophages toward the tissue‐destructive phenotype. Concomitantly, they showed aberrant phenotypic modulation of smooth muscle cells and transforming growth factor beta signaling, which are likely to participate in tissue repair. Human AD samples revealed signal transduction and activator of transcription 3 activation in adventitial macrophages adjacent to the site of tissue destruction.ConclusionsThese findings suggest that AD development is preceded by focal medial rupture, in which macrophage Socs3 maintains proper inflammatory response and differentiation of SMCs, thus promoting fibrotic healing to prevent tissue destruction and AD development. Understanding the sequence of the pathological and molecular events preceding AD development will help predict and prevent AD development and progression.

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Section: Discussionsupporting

confidence: 91%

Section: Resultssupporting

confidence: 83%

Role of Macrophage Socs3 in the Pathogenesis of Aortic Dissection

Ohno‐Urabe

Aoki

Nishihara

et al. 2018

JAHA

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“…This hypothesis was initially based on observations of Gavish et al, who reported focal ruptures of the elastic lamellae in 126 of 325 investigated histological sections that included at least part of a branch orifice, but in none of the 479 sections in between branches [3]. The branch-related hypothesis was further supported by our previous work, in which we used a novel post mortem imaging technique (PCXTM) to visualize abdominal aortic aneurysms in angiotensin II-infused mice [4]. We demonstrated that the variation in aneurysm shape, ranging from Grade I (minor dilatation without thrombus) to Grade IV (polymorphic aneurysm extending into the thoracic aorta) [37,38], was directly related to the number and location of focal mechanical failures of the tunica media that occurred in the vicinity of aortic side branches.…”

Section: Fsi Model Predictions Versus Pcxtm Observationsmentioning

confidence: 67%

“…Our high-resolution post mortem images showed that the intramural hematoma was related to ruptures in the tunica media near suprarenal side branches (such as intercostals and the superior suprarenal artery). Moreover, apparent luminal dilatation could be linked to a tear in the tunica media that appeared caudal, cranial or left lateral to the celiac artery [4].…”

Section: An Animal-specific Fsi Model Of the Abdominal Aorta In Anestmentioning

confidence: 99%

An Animal-Specific FSI Model of the Abdominal Aorta in Anesthetized Mice

et al. 2015

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Recent research has revealed that angiotensin II-induced abdominal aortic aneurysm in mice can be related to medial ruptures occurring in the vicinity of abdominal side branches.Nevertheless a thorough understanding of the biomechanics near abdominal side branches in mice is lacking. In the current work we present a mouse-specific fluid-structure interaction (FSI) model of the abdominal aorta in ApoE -/-mice that incorporates in vivo stresses. The aortic geometry was based on contrast-enhanced in vivo micro-CT images, while aortic flow boundary conditions and material model parameters were based on in vivo high-frequency ultrasound. Flow waveforms predicted by FSI simulations corresponded better to in vivo measurements than those from CFD simulations. Peak-systolic principal stresses at the inner and outer aortic wall were locally increased caudal to the celiac and left lateral to the celiac and mesenteric arteries. Interestingly, these were also the locations at which a tear in the tunica media had been observed in previous work on angiotensin II-infused mice. Our preliminary results therefore suggest that local biomechanics play an important role in the pathophysiology of branch-related ruptures in angiotensin-II infused mice. More elaborate follow-up research is needed to demonstrate the role of biomechanics and mechanobiology in a longitudinal setting.

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“…5, panel A). Moreover we have recently demonstrated the previously undetected role of small branches in the early phase of cardiovascular pathology (Trachet et al, 2014a). Therefore, we decided to include the cerebral tree and other small branches in the model, despite the lack of proper validation.…”

Section: Model Validation In Small Side Branchesmentioning

confidence: 99%

A 1D model of the arterial circulation in mice

Aslanidou

Trachet

Reymond

et al. 2016

ALTEX

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SummaryAt a time of growing concern over the ethics of animal experimentation, mouse models are still an indispensable source of insight into the cardiovascular system and its most frequent pathologies. Nevertheless, reference data on the murine cardiovascular anatomy and physiology are lacking. In this work, we developed and validated an in silico, one dimensional model of the murine systemic arterial tree consisting of 85 arterial segments. Detailed aortic dimensions were obtained in vivo from contrast-enhanced micro-computed tomography in 3 male, C57BL/6J anesthetized mice and 3 male ApoE -/-mice, all 12-weeks old. Physiological input data were gathered from a wide range of literature data. The integrated form of the Navier-Stokes equations was solved numerically to yield pressures and flows throughout the arterial network. The resulting model predictions have been validated against invasive pressure waveforms and noninvasive velocity and diameter waveforms that were measured in vivo on an independent set of 47 mice. In conclusion, we present a validated one-dimensional model of the anesthetized murine cardiovascular system that can serve as a versatile tool in the field of preclinical cardiovascular research.

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Dissecting abdominal aortic aneurysm in Ang II-infused mice: suprarenal branch ruptures and apparent luminal dilatation

Cited by 67 publications

References 40 publications

Role of Macrophage Socs3 in the Pathogenesis of Aortic Dissection

Role of Macrophage Socs3 in the Pathogenesis of Aortic Dissection

An Animal-Specific FSI Model of the Abdominal Aorta in Anesthetized Mice

A 1D model of the arterial circulation in mice

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