Two Diverse Hemodynamic Forces, a Mechanical Stretch and a High Wall Shear Stress, Determine Intracranial Aneurysm Formation

  • Hirokazu Koseki
  • Haruka Miyata
  • Satoshi Shimo
  • Nobuhiko Ohno
  • Kazuma Mifune
  • Kenjiro Shimano
  • Kimiko Yamamoto
  • Kazuhiko Nozaki
  • Hidetoshi Kasuya
  • Shuh Narumiya
  • Tomohiro AokiEmail author
Original Article


Intracranial aneurysm (IA) usually induced at a bifurcation site of intracranial arteries causes a lethal subarachnoid hemorrhage. Currently, IA is considered as a macrophage-mediated inflammatory disease triggered by a high wall shear stress (WSS) on endothelial cells. However, considered the fact that a high WSS can be observed at every bifurcation site, some other factors are required to develop IAs. We therefore aimed to clarify mechanisms underlying the initiation of IAs using a rat model. We found the transient outward bulging and excessive mechanical stretch at a prospective site of IA formation. Fibroblasts at the adventitia of IA walls were activated and produced (C-C motif) ligand 2 (CCL2) as well in endothelial cells loaded on high WSS at the earliest stage. Consistently, the mechanical stretch induced production of CCL2 in primary culture of fibroblasts and promoted migration of macrophages in a Transwell system. Our results suggest that distinct hemodynamic forces, mechanical stretch on fibroblasts and high WSS on endothelial cells, regulate macrophage-mediated IA formation.


Intracranial aneurysm Hemodynamic force Stretch Fibroblast Macrophage 



The authors thank all of their technical staff and secretaries for their kind assistance. The authors also thank the technical assistant from the Division of Electron Microscopic Study in Center for Anatomical Studies at Kyoto University Graduate School of Medicine for electron microscopy and the National BioResource Project-Rat at Kyoto University for preparing transgenic rat line.


This study was funded by the Core Research for Evolutional Science and Technology (CREST) on Mechanobiology from the Japan Agency for Medical Research and Development (AMED) (Grant No. JP18gm0810006, T. A.).

Compliance with Ethical Standards

Conflict of Interest

T. A. was supported by the Coordination Fund from the Japanese Ministry for Education, Culture, Sports, Science and Technology (MEXT) and Astellas Pharma Inc. to Kyoto University until 31th/March/2017 and S.N. is supported by a same grant. S.N. is a scientific advisor to Astellas Pharma. H. K., H. M., S. S., N.O., K. M., K. S., K. Y., K. N., and H. K. declare that they have no conflict of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. And this study was approved by the Institutional Animal Care and Use Committee of Kyoto University Graduate School of Medicine and also of National Cerebral and Cardiovascular Center. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by the Institutional Review Board of Shimizu Hospital (Kyoto, Japan, Approval No. 203). Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Hirokazu Koseki
    • 1
    • 2
    • 3
  • Haruka Miyata
    • 1
    • 3
    • 4
  • Satoshi Shimo
    • 5
  • Nobuhiko Ohno
    • 6
    • 7
  • Kazuma Mifune
    • 8
  • Kenjiro Shimano
    • 8
  • Kimiko Yamamoto
    • 9
  • Kazuhiko Nozaki
    • 4
  • Hidetoshi Kasuya
    • 2
  • Shuh Narumiya
    • 10
  • Tomohiro Aoki
    • 1
    • 3
    • 10
    Email author
  1. 1.Department of Molecular Pharmacology, Research InstituteNational Cerebral and Cardiovascular CenterOsakaJapan
  2. 2.Department of NeurosurgeryTokyo Women’s Medical University Medical Center EastTokyoJapan
  3. 3.Core Research for Evolutional Science and Technology (CREST) from Japan Agency for Medical Research and Development (AMED)Kyoto University Graduate School of MedicineKyotoJapan
  4. 4.Department of NeurosurgeryShiga University of Medical ScienceShigaJapan
  5. 5.Department of Occupational TherapyHealth Science UniversityYamanashiJapan
  6. 6.Division of Neurobiology and BioinformaticsNational Institute for Physiological SciencesAichiJapan
  7. 7.Department of AnatomyJichi Medical UniversityTochigiJapan
  8. 8.Department of Mechanical Systems EngineeringTokyo City UniversityTokyoJapan
  9. 9.System Physiology, Department of Biomedical Engineering, Graduate School of MedicineThe University of TokyoTokyoJapan
  10. 10.Alliance Laboratory for Advanced Medical Research, Medical Innovation CenterKyoto University Graduate School of MedicineKyotoJapan

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