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Absence of LTBP-3 attenuates the aneurysmal phenotype but not spinal effects on the aorta in Marfan syndrome

  • A. Korneva
  • L. Zilberberg
  • D. B. Rifkin
  • J. D. Humphrey
  • C. Bellini
Original Paper
  • 49 Downloads

Abstract

Fibrillin-1 is an elastin-associated glycoprotein that contributes to the long-term fatigue resistance of elastic fibers as well as to the bioavailability of transforming growth factor-beta (TGFβ) in arteries. Altered TGFβ bioavailability and/or signaling have been implicated in aneurysm development in Marfan syndrome (MFS), a multi-system condition resulting from mutations to the gene that encodes fibrillin-1. We recently showed that the absence of the latent transforming growth factor-beta binding protein-3 (LTBP-3) in fibrillin-1-deficient mice attenuates the fragmentation of elastic fibers and focal dilatations that are characteristic of aortic root aneurysms in MFS mice, at least to 12 weeks of age. Here, we show further that the absence of LTBP-3 in this MFS mouse model improves the circumferential mechanical properties of the thoracic aorta, which appears to be fundamental in preventing or significantly delaying aneurysm development. Yet, a spinal deformity either remains or is exacerbated in the absence of LTBP-3 and seems to adversely affect the axial mechanical properties of the thoracic aorta, thus decreasing overall vascular function despite the absence of aneurysmal dilatation. Importantly, because of the smaller size of mice lacking LTBP-3, allometric scaling facilitates proper interpretation of aortic dimensions and thus the clinical phenotype. While this study demonstrates that LTBP-3/TGFβ directly affects the biomechanical function of the thoracic aorta, it highlights that spinal deformities in MFS might indirectly and adversely affect the overall aortic phenotype. There is a need, therefore, to consider together the vascular and skeletal effects in this syndromic disease.

Keywords

Fibrillin-1 Aortic stiffness Vascular phenotype Kyphosis Aortic curvature Allometric scaling 

Notes

Acknowledgements

We thank Professor F. Ramirez, Mt. Sinai School of Medicine, for thoughtful comments, Professor D. M. Milewicz, University of Texas Medical Center—Houston, for stimulating conversations regarding the need to correct aortic diameter according to body size, and Ms. Arunika Makam for the segmentation of the CT images.

Funding

This work was supported, in part, by Grants from the NIH (P01 HL134605 to DBR, with Core C to JDH, as well as R01 HL105297 and U01 HL116323 to JDH), and The Marfan Foundation to DBR.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Supplementary material

10237_2018_1080_MOESM1_ESM.pdf (1.7 mb)
Supplementary material 1 (PDF 1696 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biomedical EngineeringYale UniversityNew HavenUSA
  2. 2.Departments of Cell Biology and MedicineNew York UniversityNew YorkUSA
  3. 3.Vascular Biology and Therapeutics ProgramYale School of MedicineNew HavenUSA
  4. 4.Department of BioengineeringNortheastern UniversityBostonUSA

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