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Munshaw, S.* ; Bruche, S.* ; Redpath, A.N.* ; Jones, A. ; Patel, J.* ; Dube, K.N.* ; Lee, R.* ; Hester, S.S.* ; Davies, R.* ; Neal, G.* ; Handa, A.* ; Sattler, M. ; Fischer, R.* ; Channon, K.M.* ; Smart, N.*

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

J. Clin. Invest. 131:e127884 (2021)
Publ. Version/Full Text DOI
Open Access Gold (Paid Option)
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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 hypothesized that Thymosin beta 4 (T beta 4) 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 platelet-derived growth factor BB (PDGF-BB) signaling and VSMC proliferation. LRP1 variants have been implicated by genome-wide association studies with risk of AAA and other arterial diseases. T beta 4-null mice displayed aortic VSMC and elastin defects that phenocopy those of LRP1 mutants, and their compromised vascular integrity predisposed them to Angiotensin II-induced aneurysm formation. Aneurysmal vessels were characterized by enhanced VSMC phenotypic modulation and augmented PDGFR-beta signaling. In vitro, enhanced sensitivity to PDGF-BB upon loss of T beta 4 was associated with dysregulated endocytosis, with increased recycling and reduced lysosomal targeting of LRP1-PDGFR-beta. Accordingly, the exacerbated aneurysmal phenotype in T beta 4-null mice was rescued upon treatment with the PDGFR-beta antagonist Imatinib. Our study identifies T beta 4 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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Publication type Article: Journal article
Document type Scientific Article
Keywords Cardiovascular Disease ; Signal Transduction ; Vascular Biology; Vascular Smooth-muscle; Receptor-related Protein; Cell-migration; Tyrosine Phosphorylation; Lrp1; Promotes; Actin; Expression; Filamin; Binding
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Quellenangaben Volume: 131, Issue: 10, Pages: , Article Number: e127884 Supplement: ,
Publisher American Society of Clinical Investigation
Publishing Place 2015 Manchester Rd, Ann Arbor, Mi 48104 Usa
Reviewing status Peer reviewed
Grants British Heart Foundation Ian Fleming Senior Basic Science Research Fellowship
Oxford Medical Research Council