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 ß4 (Tß4) 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. Tß4-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-ß signaling. In vitro, enhanced sensitivity to PDGF-BB upon loss of Tß4 was associated with dysregulated endocytosis, with increased recycling and reduced lysosomal targeting of LRP1-PDGFR-ß. Accordingly, the exacerbated aneurysmal phenotype in Tß4-null mice was rescued upon treatment with the PDGFR-ß antagonist Imatinib. Our study identifies Tß4 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.
