A Role for Thrombospondin-1 in Arterial Remodeling under Altered Wall Shear Stress

Introduction: It is well known that wall shear stress (WSS) influences arterial remodeling. We have recently demonstrated that low and oscillatory WSS (termed disturbed flow) leads to a stiffened arterial remodeling, and we... [ view full abstract ]

Introduction: It is well known that wall shear stress (WSS) influences arterial remodeling. We have recently demonstrated that low and oscillatory WSS (termed disturbed flow) leads to a stiffened arterial remodeling, and we found that thrombospondin-1 (TSP-1) was elevated in d-flow conditions. The objective of this study was to test the importance of TSP-1 in arterial remodeling in vivo in a TSP-1 knock out mouse.
Methods: TSP-1 knockout mice underwent partial carotid ligation of their left carotid arteries, and the right side was not manipulated. Serial ultrasound measurements were performed to identify changes in arterial flow, strain, and remodeling. These were then validated ex vivo by biaxial mechanical testing.
Results: TSP-1 knockout mice carotid arteries exposed to d-flow were resistant to the stiffened and inward remodeling seen in the control C57B/6 mice in vivo, and this was validated in ex vivo testing. Interestingly, the right carotid artery, which acquired a high WSS after contralateral partial carotid ligation, underwent greater outward remodeling than its C57B/6 counterpart.
Conclusions: TSP-1 mediates arterial remodeling in response to altered WSS (both high and low), and its absence leads to greater outward remodeling and a more compliant artery. The molecular signaling mechanisms of this pathway are likely to provide novel therapeutic targets for both obstructive (inward) and aneurysmal (outward) arteriopathies.