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ResearchIn-Press PreviewVascular biology Free access | 10.1172/JCI127884

Thymosin β4 protects against aortic aneurysm via endocytic regulation of growth factor signaling

Sonali Munshaw,1 Susann Bruche,1 Andia N. Redpath,1 Alisha Jones,2 Jyoti Patel,3 Karina N. Dubé,4 Regent Lee,5 Svenja S. Hester,6 Rachel Davies,1 Giles Neal,1 Ashok Handa,5 Michael Sattler,2 Roman Fischer,6 Keith M. Channon,3 and Nicola Smart1

1Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom

2Biomolecular NMR and Center for Integrated Protein Science Munich at Chemis, Technical University of Munich, Munich, Germany

3Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom

4Molecular Medicine Unit, UCL-Institute of Child Health, London, United Kingdom

5Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

6Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

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1Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom

2Biomolecular NMR and Center for Integrated Protein Science Munich at Chemis, Technical University of Munich, Munich, Germany

3Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom

4Molecular Medicine Unit, UCL-Institute of Child Health, London, United Kingdom

5Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

6Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

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1Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom

2Biomolecular NMR and Center for Integrated Protein Science Munich at Chemis, Technical University of Munich, Munich, Germany

3Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom

4Molecular Medicine Unit, UCL-Institute of Child Health, London, United Kingdom

5Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

6Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

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1Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom

2Biomolecular NMR and Center for Integrated Protein Science Munich at Chemis, Technical University of Munich, Munich, Germany

3Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom

4Molecular Medicine Unit, UCL-Institute of Child Health, London, United Kingdom

5Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

6Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

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1Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom

2Biomolecular NMR and Center for Integrated Protein Science Munich at Chemis, Technical University of Munich, Munich, Germany

3Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom

4Molecular Medicine Unit, UCL-Institute of Child Health, London, United Kingdom

5Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

6Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

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1Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom

2Biomolecular NMR and Center for Integrated Protein Science Munich at Chemis, Technical University of Munich, Munich, Germany

3Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom

4Molecular Medicine Unit, UCL-Institute of Child Health, London, United Kingdom

5Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

6Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

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1Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom

2Biomolecular NMR and Center for Integrated Protein Science Munich at Chemis, Technical University of Munich, Munich, Germany

3Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom

4Molecular Medicine Unit, UCL-Institute of Child Health, London, United Kingdom

5Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

6Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

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1Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom

2Biomolecular NMR and Center for Integrated Protein Science Munich at Chemis, Technical University of Munich, Munich, Germany

3Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom

4Molecular Medicine Unit, UCL-Institute of Child Health, London, United Kingdom

5Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

6Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

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1Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom

2Biomolecular NMR and Center for Integrated Protein Science Munich at Chemis, Technical University of Munich, Munich, Germany

3Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom

4Molecular Medicine Unit, UCL-Institute of Child Health, London, United Kingdom

5Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

6Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

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1Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom

2Biomolecular NMR and Center for Integrated Protein Science Munich at Chemis, Technical University of Munich, Munich, Germany

3Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom

4Molecular Medicine Unit, UCL-Institute of Child Health, London, United Kingdom

5Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

6Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

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1Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom

2Biomolecular NMR and Center for Integrated Protein Science Munich at Chemis, Technical University of Munich, Munich, Germany

3Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom

4Molecular Medicine Unit, UCL-Institute of Child Health, London, United Kingdom

5Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

6Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

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1Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom

2Biomolecular NMR and Center for Integrated Protein Science Munich at Chemis, Technical University of Munich, Munich, Germany

3Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom

4Molecular Medicine Unit, UCL-Institute of Child Health, London, United Kingdom

5Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

6Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

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1Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom

2Biomolecular NMR and Center for Integrated Protein Science Munich at Chemis, Technical University of Munich, Munich, Germany

3Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom

4Molecular Medicine Unit, UCL-Institute of Child Health, London, United Kingdom

5Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

6Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

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1Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom

2Biomolecular NMR and Center for Integrated Protein Science Munich at Chemis, Technical University of Munich, Munich, Germany

3Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom

4Molecular Medicine Unit, UCL-Institute of Child Health, London, United Kingdom

5Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

6Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

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1Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom

2Biomolecular NMR and Center for Integrated Protein Science Munich at Chemis, Technical University of Munich, Munich, Germany

3Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom

4Molecular Medicine Unit, UCL-Institute of Child Health, London, United Kingdom

5Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

6Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

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Published March 30, 2021 - More info

J Clin Invest. https://doi.org/10.1172/JCI127884.
Copyright © 2021, American Society for Clinical Investigation
Published March 30, 2021 - Version history
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Abstract

Vascular stability and tone are maintained by contractile smooth muscle cells (VSMCs). However, injury-induced growth factors stimulate a contractile-synthetic phenotypic modulation which increases susceptibility to abdominal aortic aneurysm (AAA). As a regulator of embryonic VSMC differentiation, we hypothesised that Thymosin β4 (Tβ4) may function to maintain healthy vasculature throughout postnatal life. This was supported by the identification of an interaction with Low density lipoprotein receptor related protein 1 (LRP1), an endocytic regulator of PDGF-BB signalling and VSMC proliferation. LRP1 variants have been implicated by genome-wide association studies with risk of AAA and other arterial diseases. Tβ4-null mice displayed aortic VSMC and elastin defects, phenocopying LRP1 mutants, and their compromised vascular integrity predisposed to Angiotensin II-induced aneurysm formation. Aneurysmal vessels were characterised by enhanced VSMC phenotypic modulation and augmented platelet-derived growth factor (PDGF) receptor (PDGFR)β signalling. In vitro, enhanced sensitivity to PDGF-BB, upon loss of Tβ4, associated with dysregulated endocytosis, with increased recycling and reduced lysosomal targeting of LRP1-PDGFRβ. Accordingly, the exacerbated aneurysmal phenotype in Tβ4-null mice was rescued upon treatment with the PDGFRβ antagonist, Imatinib. Our study identifies Tβ4 as a key regulator of LRP1 for maintaining vascular health and provides insights into the mechanisms of growth factor-controlled VSMC phenotypic modulation underlying aortic disease progression.

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graphical abstract
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  • Version 1 (March 30, 2021): In-Press Preview
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