Krishna, Smriti Murali, Seto, Sai Wang, Jose, Roby, Li, Jiaze, Moxon, Joseph, Clancy, Paula, Crossman, David J., Norman, Paul, Emeto, Theophilus I., and Golledge, Jonathan (2017) High serum thrombospondin-1 concentration is associated with slower abdominal aortic aneurysm growth and deficiency promotes angiotensin-II induced aneurysm in mice. Clinical Science, 131 (12). pp. 1261-1281.

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Abstract

Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Thrombospondin-1 (TSP-1; gene Thbs1) is a member of the matricellular protein family important in the control of extracellular matrix remodeling. In this study, the association of serum TSP-1 concentration with AAA progression was assessed in 276 men that underwent repeat ultrasound for a median 5.5 years. AAA growth was negatively correlated with serum TSP-1 concentration ( Spearman's rho -0.129, P=0.033 ). Men with TSP-1 in the highest quartile had a reduced likelihood of AAA growth greater than median during follow-up (OR 0.40; 95% CI, 0.19-0.84, P=0.016 , adjusted for other risk factors). Immunohistochemical staining for TSP-1 was reduced in AAA body tissues compared to the relatively normal AAA neck. To further assess the role of TSP-1 in AAA progression, combined TSP-1 and apolipoprotein deficient ( Thbs1-/-ApoE-/- ,n=20) and control mice ( ApoE-/- , n=20) were infused subcutaneously with angiotensin II (AngII) for 28 days. Following AngII infusion, Thbs1-/- ApoE-/- mice had larger AAAs by ultrasound ( P=0.024 ) and ex vivo morphometry measurement ( P=0.006 ). The Thbs1-/-ApoE-/- mice also showed increased elastin filament degradation along with elevated systemic levels and aortic expression of matrix metalloproteinase (MMP)-9. Suprarenal aortic segments and vascular smooth muscle cells isolated from Thbs1-/-ApoE-/- mice showed reduced Collagen 3A1 gene expression. Furthermore, Thbs1-/-ApoE-/- mice had reduced aortic expression of low density lipoprotein receptor-related protein 1. Collectively, findings from this study suggest that TSP-1 deficiency promotes maladaptive remodeling of the extracellular matrix leading to accelerated AAA progression.

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