Abstract
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 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 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. Tβ4-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-β signaling. In vitro, enhanced sensitivity to PDGF-BB upon loss of Tβ4 was associated with dysregulated endocytosis, with increased recycling and reduced lysosomal targeting of LRP1–PDGFR-β. Accordingly, the exacerbated aneurysmal phenotype in Tβ4-null mice was rescued upon treatment with the PDGFR-β 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.
Highlights
The integrity of the blood vessel wall is key to resisting the shear forces of flowing blood and preventing aneurysmal dilatation and rupture
Seeking insight into the underlying mechanisms, we identified an interaction between Thymosin β4 (Tβ4) and low density lipoprotein receptor related protein 1 (LRP1), which functions in VSMC development and protection by regulating growth factor signaling [12, 13] and ECM remodeling [14, 15]
Accelerated disease progression was characterized by augmented contractile-synthetic VSMC switching and underpinned by dysregulated PDGFR-β signaling, which results from a failure to functionally regulate trafficking of PDGFR-β and coreceptor LRP1
Summary
The integrity of the blood vessel wall is key to resisting the shear forces of flowing blood and preventing aneurysmal dilatation and rupture. Endothelial damage triggers macrophage infiltration, leading to compromised vascular stability and susceptibility to aortic aneurysm. Prevalence of aortic aneurysm is 5% among the elderly and, with no pharmacological options, treatment involves a high-risk surgical procedure. While risk of rupture is low for small, asymptomatic aneurysms, risk escalates with increasing aortic dilatation, and rupture is invariably catastrophic, with a mortality of 50%–80% [1]. Genome-wide association studies (GWAS) have provided important insights into genetic predisposition for abdominal aortic aneurysm (AAA). A major challenge in the postgenomic era is to elucidate the molecular mechanisms through which GWAS hits influence pathogenesis [2, 3]
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