Thymosin β4 mediates vascular protection via regulation of low density lipoprotein receptor related protein 1 (LRP1)

Background and Aims: Thymosin β4 (Tβ4), is a small peptide implicated in mural VSMC differentiation in developing embryo. A proportion of Tβ4KO embryos die with vascular haemorrhage and surviving adults display aortic VSMC and elastin defects. We found an interaction between LRP1 and Tβ4. LRP1 an endocytic co regulator of PDGF-BB signalling was associated by GWAS with risk of abdominal aortic aneurysm (AAA) and shown, in animal studies, to protect against AAA and atherosclerosis. Hypothesis: Tβ4 controls vasculoprotective signalling by regulating endocytosis of LRP1. Methods: Predisposition to vascular disease was confirmed in global, endothelial- and VSMC- specific Tβ4KO mouse models of AAA and atherosclerosis. Inflammation, ECM composition and elastin were analysed, alongside VSMC phenotype and signalling. We used surface biotinylation assays to track LRP1 distribution in Tβ4 knockdown aortic VSMCs. Finally, we evaluated the potential of exogenous Tβ4 to protect against vascular disease. Results: Tβ4KO mice displayed increased susceptibility to AAA, ranging from aortic dilation to medial dissection in Conclusions: We identify Tβ4 as a key regulator of LRP1-PDGFRb endocytic signalling, for maintaining VSMC differentiation and vascular health. Tβ4 may emerge as a promising candidate for treatment of vascular disease.