PuSH - Publikationsserver des Helmholtz Zentrums München: Thymosin <strong>β</strong>4 protects against aortic aneurysm via endocytic regulation of growth factor signaling.

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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)

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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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