PXD024162

PXD024162 is an original dataset announced via ProteomeXchange.

Title	Thymosin 4 protects against aortic aneurysm via endocytic regulation of growth factor signalling
Description	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. T4-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 T4-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.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:51:58.272.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Svenja Hester
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-02-12 06:07:45	ID requested
1	2021-05-21 05:14:22	announced
⏵ 2	2023-11-14 08:51:58	announced	2023-11-14: Updated project metadata.

Dataset with its publication pending

submitter keyword: smooth muscle cells , LRP1LRP1 , Thymosin β4 ,Vascular stability, endocytosis,abdominal aortic aneurysm, PDGFR)β signalling

Professor Roman Fischer
contact affiliation	University of Oxford, Nuffield Department of Medicine, Centre for Medicines Discovery
contact email	roman.fischer@ndm.ox.ac.uk
lab head
Svenja Hester
contact affiliation	Nuffield Department of Medicine
contact email	svenja.hester@ndm.ox.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024162
     1. Label: PRIDE project
     2. Name: Thymosin 4 protects against aortic aneurysm via endocytic regulation of growth factor signalling