Co-localization of microstructural damage and excessive mechanical strain at aortic branches in angiotensin-II-infused mice

  • Lydia AslanidouEmail author
  • Mauro Ferraro
  • Goran Lovric
  • Matthew R. Bersi
  • Jay D. Humphrey
  • Patrick Segers
  • Bram Trachet
  • Nikos Stergiopulos
Original Paper


Animal models of aortic aneurysm and dissection can enhance our limited understanding of the etiology of these lethal conditions particularly because early-stage longitudinal data are scant in humans. Yet, the pathogenesis of often-studied mouse models and the potential contribution of aortic biomechanics therein remain elusive. In this work, we combined micro-CT and synchrotron-based imaging with computational biomechanics to estimate in vivo aortic strains in the abdominal aorta of angiotensin-II-infused ApoE-deficient mice, which were compared with mouse-specific aortic microstructural damage inferred from histopathology. Targeted histology showed that the 3D distribution of micro-CT contrast agent that had been injected in vivo co-localized with precursor vascular damage in the aortic wall at 3 days of hypertension, with damage predominantly near the ostia of the celiac and superior mesenteric arteries. Computations similarly revealed higher mechanical strain in branching relative to non-branching regions, thus resulting in a positive correlation between high strain and vascular damage in branching segments that included the celiac, superior mesenteric, and right renal arteries. These results suggest a mechanically driven initiation of damage at these locations, which was supported by 3D synchrotron imaging of load-induced ex vivo delaminations of angiotensin-II-infused suprarenal abdominal aortas. That is, the major intramural delamination plane in the ex vivo tested aortas was also near side branches and specifically around the celiac artery. Our findings thus support the hypothesis of an early mechanically mediated formation of microstructural defects at aortic branching sites that subsequently propagate into a macroscopic medial tear, giving rise to aortic dissection in angiotensin-II-infused mice.


Angiotensin-II Aortic dissection Biomechanics Aortic strain Synchrotron 



The authors thank the EPFL Histology Facility for staining the histological sections. This work was supported, in part, by the Swiss National Science Foundation (SNF) Grant CR23I2_163370, Research Foundation-Flanders (FWO) fellowship 12A5816N, Research Foundation-Flanders (FWO) project G086917N, and National Institutes of Health (NIH) Grant U01 HL142518. We further acknowledge the Paul Scherrer Institute, Villigen, Switzerland, for provision of synchrotron radiation beamtime at the X02DA TOMCAT beamline of the Swiss Light Source.


  1. Adelsperger AR, Phillips EH, Ibriga HS, Craig BA, Green LA, Murphy MP, Goergen CJ (2018) Development and growth trends in angiotensin II-induced murine dissecting abdominal aortic aneurysms. Physiol Rep 6:e13668. CrossRefGoogle Scholar
  2. Ayachit U (2015) The paraview guide: a parallel visualization application. Kitware Inc, New YorkGoogle Scholar
  3. Bellini C, Ferruzzi J, Roccabianca S, Di Martino ES, Humphrey JD (2014) A microstructurally motivated model of arterial wall mechanics with mechanobiological implications. Ann Biomed Eng 42:488–502. CrossRefGoogle Scholar
  4. Bellini C, Kristofik NJ, Bersi MR, Kyriakides TR, Humphrey JD (2017) A hidden structural vulnerability in the thrombospondin-2 deficient aorta increases the propensity to intramural delamination. J Mech Behav Biomed Mater 71:397–406. CrossRefGoogle Scholar
  5. Bersi MR, Bellini C, Di Achille P, Humphrey JD, Genovese K, Avril S (2016) Novel methodology for characterizing regional variations in the material properties of murine aortas. J Biomech Eng 138:071005. CrossRefGoogle Scholar
  6. Bersi MR, Khosravi R, Wujciak AJ, Harrison DG, Humphrey JD (2017) Differential cell-matrix mechanoadaptations and inflammation drive regional propensities to aortic fibrosis, aneurysm or dissection in hypertension. J R Soc Interface 14:20170327CrossRefGoogle Scholar
  7. Bonfanti M, Balabani S, Greenwood JP, Puppala S, Homer-Vanniasinkam S, Díaz-Zuccarini V (2017) Computational tools for clinical support: a multi-scale compliant model for haemodynamic simulations in an aortic dissection based on multi-modal imaging data. J R Soc Interface 14:20170632CrossRefGoogle Scholar
  8. Cao RY, Amand T, Ford MD, Piomelli U, Funk CD (2010) The murine angiotensin II-induced abdominal aortic aneurysm model: rupture risk and inflammatory progression patterns. Front Pharmacol 1:9. Google Scholar
  9. Cassis LA et al (2009) ANG II infusion promotes abdominal aortic aneurysms independent of increased blood pressure in hypercholesterolemic mice. Am J Physiol Heart Circ Physiol 296:H1660–H1665. CrossRefGoogle Scholar
  10. Chen HY et al (2016) Editor’s choice—fluid-structure interaction simulations of aortic dissection with bench validation. Eur J Vasc Endovasc Surg 52:589–595. CrossRefGoogle Scholar
  11. Chi Q, He Y, Luan Y, Qin K, Mu L (2017) Numerical analysis of wall shear stress in ascending aorta before tearing in type A aortic dissection. Comput Biol Med 89:236–247. CrossRefGoogle Scholar
  12. Daugherty A, Cassis LA (2004) Mouse models of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 24:429–434. CrossRefGoogle Scholar
  13. Daugherty A, Manning MW, Cassis LA (2000) Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E–deficient mice. J Clin Investig 105:1605–1612. CrossRefGoogle Scholar
  14. De Wilde D, Trachet B, De Meyer GRY, Segers P (2016) Shear stress metrics and their relation to atherosclerosis: an in vivo follow-up study in atherosclerotic mice. Ann Biomed Eng 44:2327–2338. CrossRefGoogle Scholar
  15. Farotto D, Segers P, Meuris B, Vander Sloten J, Famaey N (2018) The role of biomechanics in aortic aneurysm management: requirements, open problems and future prospects. J Mech Behav Biomed Mater 77:295–307. CrossRefGoogle Scholar
  16. Favreau JT et al (2012) Murine ultrasound imaging for circumferential strain analyses in the angiotensin II abdominal aortic aneurysm model. J Vasc Surg 56:462–469. CrossRefGoogle Scholar
  17. Ferraro M, Trachet B, Aslanidou L, Fehervary H, Segers P, Stergiopulos N (2018) Should we ignore what we cannot measure? How non-uniform stretch, non-uniform wall thickness and minor side branches affect computational aortic biomechanics in mice. Ann Biomed Eng 46:159–170. CrossRefGoogle Scholar
  18. Ferruzzi J et al (2016) Pharmacologically improved contractility protects against aortic dissection in mice with disrupted transforming growth factor-β signaling despite compromised extracellular matrix properties. Arterioscler Thromb Vasc Biol 36:919–927. CrossRefGoogle Scholar
  19. Ferruzzi J, Di Achille P, Tellides G, Humphrey JD (2018) Combining in vivo and in vitro biomechanical data reveals key roles of perivascular tethering in central artery function. PLoS ONE 13:e0201379. CrossRefGoogle Scholar
  20. Ford MD, Black AT, Cao RY, Funk CD, Piomelli U (2011) Hemodynamics of the mouse abdominal aortic aneurysm. J Biomech Eng 133:121008–121009. CrossRefGoogle Scholar
  21. Gaul RT, Nolan DR, Lally C (2018) The use of small angle light scattering in assessing strain induced collagen degradation in arterial tissue ex vivo. J Biomech 81:155–160. CrossRefGoogle Scholar
  22. Gavish L et al (2012) Low level laser arrests abdominal aortic aneurysm by collagen matrix reinforcement in apolipoprotein E-deficient mice. Lasers Surg Med 44:664–674. CrossRefGoogle Scholar
  23. Gavish L et al (2014) Inadequate reinforcement of transmedial disruptions at branch points subtends aortic aneurysm formation in apolipoprotein-E-deficient mice. Cardiovasc Pathol 23:152–159. CrossRefGoogle Scholar
  24. Genovese K, Collins MJ, Lee YU, Humphrey JD (2012) Regional finite strains in an angiotensin-II induced mouse model of dissecting abdominal aortic aneurysms. Cardiovasc Eng Technol 3:194–202. CrossRefGoogle Scholar
  25. Goergen CJ, Johnson BL, Greve JM, Taylor CA, Zarins CK (2007) Increased anterior abdominal aortic wall motion: possible role in aneurysm pathogenesis and design of endovascular devices. J Endovasc Therapy 14:574–584. CrossRefGoogle Scholar
  26. Goergen CJ et al (2010) In vivo quantification of murine aortic cyclic strain, motion, and curvature: implications for abdominal aortic aneurysm growth. J Magn Reson Imaging 32:847–858. CrossRefGoogle Scholar
  27. Goergen CJ et al (2011) Influences of aortic motion and curvature on vessel expansion in murine experimental aneurysms. Arterioscler Thromb Vasc Biol 31:270–279. CrossRefGoogle Scholar
  28. Haggerty CM, Mattingly AC, Gong MC, Su W, Daugherty A, Fornwalt BK (2015) Telemetric blood pressure assessment in angiotensin II-Infused apoe-/- mice: 28 day natural history and comparison to tail-cuff measurements. PLoS ONE 10:e0130723. CrossRefGoogle Scholar
  29. Humphrey JD, Holzapfel GA (2012) Mechanics, mechanobiology, and modeling of human abdominal aorta and aneurysms. J Biomech 45:805–814. CrossRefGoogle Scholar
  30. Laroumanie F et al (2018) LNK deficiency promotes acute aortic dissection and rupture. JCI Insight 3:e122558. CrossRefGoogle Scholar
  31. Leemans EL, Willems TP, van der Laan MJ, Slump CH, Zeebregts CJ (2016) Biomechanical indices for rupture risk estimation in abdominal aortic aneurysms. J Endovasc Therapy 24:254–261. CrossRefGoogle Scholar
  32. Manopoulos C, Karathanasis I, Kouerinis I, Angouras DC, Lazaris A, Tsangaris S, Sokolis DP (2018) Identification of regional/layer differences in failure properties and thickness as important biomechanical factors responsible for the initiation of aortic dissections. J Biomech 80:102–110. CrossRefGoogle Scholar
  33. Nathan DP et al (2011) Pathogenesis of acute aortic dissection: a finite element stress analysis. Ann Thorac Surg 91:458–463. CrossRefGoogle Scholar
  34. Perrin D, Badel P, Orgeas L, Geindreau C, du Roscoat S, Albertini J-N, Avril S (2016) Patient-specific simulation of endovascular repair surgery with tortuous aneurysms requiring flexible stent-grafts. J Mech Behav Biomed Mater 63:86–99. CrossRefGoogle Scholar
  35. Phillips EH, Achille PD, Bersi MR, Humphrey JD, Goergen CJ (2017) Multi-modality imaging enables detailed hemodynamic simulations in dissecting aneurysms in mice. IEEE Trans Med Imaging 36:1297–1305. CrossRefGoogle Scholar
  36. Phillips EH, Lorch AH, Durkes AC, Goergen CJ (2018) Early pathological characterization of murine dissecting abdominal aortic aneurysms APL. Bioengineering 2:046106. CrossRefGoogle Scholar
  37. Saraff K, Babamusta F, Cassis LA, Daugherty A (2003) Aortic dissection precedes formation of aneurysms and atherosclerosis in angiotensin II-infused, apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 23:1621–1626. CrossRefGoogle Scholar
  38. Sho E, Sho M, Nanjo H, Kawamura K, Masuda H, Dalman RL (2004) Hemodynamic regulation of CD34+ cell localization and differentiation in experimental aneurysms. Arterioscler Thromb Vasc Biol 24:1916–1921. CrossRefGoogle Scholar
  39. The Vascular Modeling Toolkit website,
  40. Trachet B et al (2011) An integrated framework to quantitatively link mouse-specific hemodynamics to aneurysm formation in angiotensin II-infused Apoe −/− mice. Ann Biomed Eng 39:2430. CrossRefGoogle Scholar
  41. Trachet B et al (2014) Dissecting abdominal aortic aneurysm in Ang II-infused mice: suprarenal branch ruptures and apparent luminal dilatation. Cardiovasc Res 105:213–222. CrossRefGoogle Scholar
  42. Trachet B, Bols J, Degroote J, Verhegghe B, Stergiopulos N, Vierendeels J, Segers P (2015a) An animal-specific FSI model of the abdominal aorta in anesthetized mice. Ann Biomed Eng 43:1298–1309. CrossRefGoogle Scholar
  43. Trachet B, Fraga-Silva RA, Jacquet PA, Stergiopulos N, Segers P (2015b) Incidence, severity, mortality, and confounding factors for dissecting AAA detection in angiotensin II-infused mice: a meta-analysis. Cardiovasc Res 108:159–170. CrossRefGoogle Scholar
  44. Trachet B, Fraga-Silva RA, Piersigilli A, Segers P, Stergiopulos N (2015c) Dissecting abdominal aortic aneurysm in Angiotensin II-infused mice: the importance of imaging. Curr Pharm Des 21(28):4049–4060CrossRefGoogle Scholar
  45. Trachet B et al (2017) Angiotensin II infusion into ApoE-/- mice: a model for aortic dissection rather than abdominal aortic aneurysm? Cardiovasc Res 113:1230–1242. CrossRefGoogle Scholar
  46. Trachet B et al (2018) Synchrotron-based phase contrast imaging of cardiovascular tissue in mice—grating interferometry or phase propagation? Biomed Phys Eng Express 5:015010CrossRefGoogle Scholar
  47. Vorp DA (2007) Biomechanics of abdominal aortic aneurysm. J Biomech 40:1887–1902. CrossRefGoogle Scholar
  48. Wang Y-X et al (2001) Angiotensin II increases urokinase-type plasminogen activator expression and induces aneurysm in the abdominal aorta of apolipoprotein e-deficient mice. Am J Pathol 159:1455–1464. CrossRefGoogle Scholar
  49. Xie X, Lu H, Moorleghen JJ, Howatt DA, Rateri DL, Cassis LA, Daugherty A (2012) Doxycycline does not influence established abdominal aortic aneurysms in angiotensin II-infused mice. PLoS ONE 7:e46411. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institute of BioengineeringÉcole Polytechnique Fédérale de LausanneLausanneSwitzerland
  2. 2.Centre d’Imagerie BioMédicaleÉcole Polytechnique Fédérale de LausanneLausanneSwitzerland
  3. 3.Swiss Light Source, Paul Scherrer InstituteVilligenSwitzerland
  4. 4.Department of Biomedical EngineeringYale UniversityNew HavenUSA
  5. 5.Department of Biomedical EngineeringVanderbilt UniversityNashvilleUSA
  6. 6.bioMMeda, Ghent UniversityGhentBelgium

Personalised recommendations