ThymosinB4- A novel regulator of Low density lipoprotein receptor related protein 1(LRP1) in vascular disease

Cardiovascular diseases, including atherosclerosis and abdominal aortic aneurysm (AAA), are amongst the foremost causes of global morbidity. Despite decades of research, the mechanisms underlying disease progression remain unresolved, resulting in a lack of efficient pharmacological therapies to prevent disease progression. Maintaining vascular stability is fundamental to protect against disease pathogenesis. Contractile smooth muscle cells (VSMCs) and elastin-rich extracellular matrix (ECM) are major determinants of vascular stability and tone. Injury-induced growth factors stimulate phenotypic modulation of VSMCs, from their quiescent contractile state to a more active, synthetic phenotype, that proliferate, migrate and accelerate progression of atherosclerosis and AAA. Inhibiting VSMC phenotypic transformation has thus been shown to attenuate disease progression. Thymosin β4 (Tβ4), a small actin-binding peptide, promotes VSMC differentiation during development and preserves VSMC differentiation postnatally in the healthy aorta. Tβ4 interacts with Low density lipoprotein receptor related protein 1 (LRP1), an endocytic regulator of PDGFRβ signalling in VSMCs, and LRP1 variants have been identified by GWAS as major risk loci for AAA and coronary artery disease. We hypothesised that Tβ4 may function to protect against vascular disease via LRP1 mediated growth factor signalling. Using well-characterised models of atherosclerosis and AAA, increased susceptibility to disease was confirmed in mice lacking Tβ4. Tβ4-null mice displayed increased susceptibility to AAA, ranging from aortic dilation to overt medial dissection and rupture in <5 days. Similarly, in the aortic root and descending aorta, mice lacking Tβ4 on ApoE-/- background develop more unstable atherosclerotic plaques, with large necrotic cores. Diseased vessels were characterised by enhanced contractile-synthetic VSMC switching and increased elastin degradation, underpinned by augmented LRP1-PDGFRβ signalling. Primary aortic VSMCs lacking Tβ4 show enhanced sensitivity to PDGF-BB, coinciding with dysregulated intra-cellular trafficking, leading to increased recycling of LRP1-PDGFRβ and reduced lysosomal targeting. Given that exogenous Tβ4 can regulate endocytosis, and due to the known anti-fibrotic, anti-inflammatory and anti-apoptotic properties of Tβ4, the therapeutic potential of exogenously administered Tβ4 was evaluated in the AAA model. Simultaneous administration of Tβ4 and AngII in C57BL/6J mice reduced aneurysms and the associated elastin degradation, preserved contractile VSMC phenotype, and attenuated activation of PDGFRβ. This research identifies endogenous Tβ4 as a novel regulator of LRP1 in the aorta to protect against atherosclerosis and AAA and reveals the potential for using Tβ4 as a therapeutic agent to protect against vascular disease. However, further studies are required to validate these findings and to elucidate the exact molecular mechanisms through which protection is achieved.

Keywords: Mice lacking Tβ4  show increased susceptibility to atherosclerosis and AAA
Modulated smooth muscle cells (SMCs) downregulate the expression of Tmsb4x
Tβ4 regulates LRP1-PDGFRβ signalling provides vascular protection in vascular diseases
Advisor: Smart, N