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Altered tissue behavior of a non-aneurysmal descending thoracic aorta in the mouse model of Marfan syndrome

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Abstract

Aortic aneurysm is predominantly found in the ascending aorta in patients with Marfan syndrome (MFS). However, descending aortic disease has emerged as a problem since people are living longer because of improved medical and surgical management of the ascending aorta. Diagnostic procedures before disease onset and the mechanisms involved in the transition of normal aortic tissue to aneurysm remain unclear. We determined signs of descending aortic disease before disease onset in mice with a mutation in the fibrillin 1 gene (Fbn1 +/C1039G), a validated mouse model of disease susceptibility and progression of aortic aneurysm of MFS. We analyzed a tubular unfixed non-aneurysmal descending thoracic aorta from 8-month-old wild-type and Fbn1 +/C1039G mice by a tubular biaxial tester that works in conjunction with a two-photon nonlinear microscope. Fbn1 +/C1039G mouse aorta was more compliant in the circumferential direction. Two-photon imaging showed defective organization of adventitial collagen fibers in the pressurized aortas of Fbn1 +/C1039G mice. Moreover, disruption in the elastic lamina was noted in the absence of aneurysms in pressurized aortas but not unpressurized aortas of Fbn1 +/C1039G mice. At the molecular level, this altered tissue behavior in non-aneurysmal descending aortas of Fbn1 +/C1039G mice was accompanied by an increasing trend of canonical but not noncanonical, transforming growth factor-β (TGFβ) signaling. Finally, assays of in vitro collagen lattice formation in mouse wild-type and TGFβ1-deficient embryonic fibroblasts indicate that TGFβ1 can regulate collagen organization. The ability to reveal the presence of altered biomechanics and microstructure coupled with subtle changes in TGFβ signaling provides a novel surrogate measure of tissue susceptibility to aneurysm before disease onset.

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Acknowledgments

We thank Drs. Paige Snider and Simon Conway (Indiana University-Purdue University) for providing technical help with collagen contraction assays.

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Authors and Affiliations

  1. Graduate Interdisciplinary Program of Biomedical Engineering, University of Arizona, Tucson, Ariz., USA

    Darren Haskett

  2. Howard Hughes Medical Institute, Baltimore, Md., USA

    Jefferson J. Doyle & Harry C. Dietz

  3. BIO5 Institute, University of Arizona, Tucson, Ariz., USA

    Connie Gard, Corbie Ball, Mark A. Estabrook, Alejandra C. Encinas, Urs Utzinger, Jonathan P. Vande Geest & Mohamad Azhar

  4. Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Ariz., USA

    Hwudaurw Chen & Mohamad Azhar

  5. Department of Aerospace and Mechanical Engineering, University of Arizona, Tucson, Ariz., USA

    Jonathan P. Vande Geest

  6. Department of Biomedical Engineering, University of Arizona, Tucson, Ariz., USA

    Urs Utzinger & Jonathan P. Vande Geest

  7. 1656 E Mabel Street, PO Box 245217, Tucson, Ariz., USA

    Mohamad Azhar

Authors
  1. Darren Haskett
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  2. Jefferson J. Doyle
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  3. Connie Gard
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  4. Hwudaurw Chen
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  5. Corbie Ball
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  6. Mark A. Estabrook
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  7. Alejandra C. Encinas
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  8. Harry C. Dietz
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  9. Urs Utzinger
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  10. Jonathan P. Vande Geest
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  11. Mohamad Azhar
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Corresponding author

Correspondence to Mohamad Azhar.

Additional information

This study was supported, in part, by the National Institutes of Health (grants HL92508, HL105280), The Stephen Michael Schneider & The William J. "Billy" Gieszl Investigator Award (University of Arizona), Arizona Biomedical Research Commission (no. 0901), the American Heart Association-Grant in Aid (10GRNT4580045) and the National Science Foundation (grant 0644570). Imaging was performed on an NIH-sponsored shared device (NIH/NCRR S10RR023737).

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Haskett, D., Doyle, J.J., Gard, C. et al. Altered tissue behavior of a non-aneurysmal descending thoracic aorta in the mouse model of Marfan syndrome. Cell Tissue Res 347, 267–277 (2012). https://doi.org/10.1007/s00441-011-1270-y

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  • DOI: https://doi.org/10.1007/s00441-011-1270-y

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