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Asymmetric Cell–Matrix and Biomechanical Abnormalities in Elastin Insufficiency Induced Aortopathy

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Abstract

Aortopathy is characterized by vascular smooth muscle cell (VSMC) abnormalities and elastic fiber fragmentation. Elastin insufficient (Eln +/−) mice demonstrate latent aortopathy similar to human disease. We hypothesized that aortopathy manifests primarily in the aorto-pulmonary septal (APS) side of the thoracic aorta due to asymmetric cardiac neural crest (CNC) distribution. Anatomic (aortic root vs. ascending aorta) and molecular (APS vs. non-APS) regions of proximal aorta tissue were examined in adult and aged wild type (WT) and mutant (Eln +/−) mice. CNC, VSMCs, elastic fiber architecture, proteoglycan expression, morphometrics and biomechanical properties were examined using histology, 3D reconstruction, micropipette aspiration and in vivo magnetic resonance imaging (MRI). In the APS side of Eln +/− aorta, Sonic Hedgehog (SHH) is decreased while SM22 is increased. Elastic fiber architecture abnormalities are present in the Eln +/− aortic root and APS ascending aorta, and biglycan is increased in the aortic root while aggrecan is increased in the APS aorta. The Eln +/− ascending aorta is stiffer than the aortic root, the APS side is thicker and stiffer than the non-APS side, and significant differences in the individual aortic root sinuses are observed. Asymmetric structure–function abnormalities implicate regional CNC dysregulation in the development and progression of aortopathy.

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Abbreviations

APS:

Aorto-pulmonary septum

CNC:

Cardiac neural crest

ECM:

Extracellular matrix

EFF:

Elastic fiber fragmentation

Eln −/− :

Homozygous deletion of elastin gene

Eln +/− :

Heterozygous deletion of elastin gene

IOD:

Integrated optical density

MRI:

Magnetic resonance imaging

MRSD:

Maximum rate of systolic distension

PTA:

Persistent truncus arteriosus

SHH:

Sonic hedgehog

TAA:

Thoracic aortic aneurysm

VSMC:

Vascular smooth muscle cell

WT:

Wild type

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Acknowledgments

We thank Amy Opoka for her assistance. We also thank Dr. Dean Y. Li (University of Utah) for providing the elastin knockout mice and Dr. Robert P. Mecham (Washington University) for helpful discussions. Present address for Varun K. Krishnamurthy: Department of Bioengineering, Rice University, Houston, TX 77005, USA. This work was supported by the AHA 11PRE7210044 (VKK), NIH HL086856-01 (RLG), NIH HL085122 (RBH), and Cincinnati Children’s Research Foundation (RBH).

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Authors and Affiliations

  1. Division of Cardiology, the Heart Institute, Cincinnati Children’s Hospital Medical Center, 240 Albert Sabin Way, MLC 7020, Cincinnati, OH, 45229, USA

    Varun K. Krishnamurthy & Robert B. Hinton

  2. Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH, 45221, USA

    Varun K. Krishnamurthy & Daria A. Narmoneva

  3. Department of Biomedical Engineering, University of South Carolina, Columbia, SC, 29208, USA

    Ashlie N. Evans & Richard L. Goodwin

  4. Division of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA

    Janaka P. Wansapura

  5. Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA

    Hanna Osinska

  6. Department of Cell Biology and Anatomy, University of South Carolina, Columbia, SC, 29208, USA

    Kelsey E. Maddy & Stefanie V. Biechler

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  1. Varun K. Krishnamurthy
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Associate Editor Jane Grande-Allen oversaw the review of this article.

Varun K. Krishnamurthy and Ashlie N. Evans contributed equally to this work.

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Krishnamurthy, V.K., Evans, A.N., Wansapura, J.P. et al. Asymmetric Cell–Matrix and Biomechanical Abnormalities in Elastin Insufficiency Induced Aortopathy. Ann Biomed Eng 42, 2014–2028 (2014). https://doi.org/10.1007/s10439-014-1072-y

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