Thymosin?4 preserves vascular smooth muscle phenotype in atherosclerosis via regulation of low density lipoprotein related protein 1 (LRP1)

Atherosclerosis is a progressive, degenerative vascular disease and a leading cause of morbidity and mortality. In response to endothelial damage, platelet derived growth factor (PDGF)-BB induced phenotypic modulation of medial smooth muscle cells (VSMCs) promotes atherosclerotic lesion formation and destabilisation of the vessel wall. VSMC sensitivity to PDGF-BB is determined by endocytosis of Low density lipoprotein receptor related protein 1 (LRP1)-PDGFR beta complexes to balance receptor recycling with lysosomal degradation. Consequently, LRP1 is implicated in various arterial diseases. Having identified T beta 4 as a regulator of LRP1-mediated endocy-tosis to protect against aortic aneurysm, we sought to determine whether T beta 4 may additionally function to protect against atherosclerosis, by regulating LRP1-mediated growth factor signalling. By single cell tran-scriptomic analysis, Tmsb4x, encoding T beta 4, strongly correlated with contractile gene expression and was significantly down-regulated in cells that adopted a modulated phenotype in atherosclerosis. We assessed sus-ceptibility to atherosclerosis of global T beta 4 knockout mice using the ApoE-/-hypercholesterolaemia model. Inflammation, elastin integrity, VSMC phenotype and signalling were analysed in the aortic root and descending aorta. T beta 4KO; ApoE-/-mice develop larger atherosclerotic plaques than control mice, with medial layer degen-eration characterised by accelerated VSMC phenotypic modulation. Defects in T beta 4KO; ApoE-/-mice phenocopied those in VSMC-specific LRP1 nulls and, moreover, were underpinned by hyperactivated LRP1-PDGFR beta signalling. We identify an atheroprotective role for endogenous T beta 4 in maintaining differentiated VSMC phenotype via LRP1-mediated PDGFR beta signalling.

Automated summary

In a hypercholesterolemic model, knockout of the T beta 4 gene exacerbates atherosclerotic lesions, induces phenotypic changes in vascular smooth muscle cells, and is associated with hyperactivation of the low density lipoprotein receptor-related protein 1 (LRP1)-mediated growth factor signaling pathway.