Cell-Specific Functions of ADAM17 Regulate the Progression of Thoracic Aortic Aneurysm
Rationale: Disintegrin and metalloproteinase-17 (ADAM17) is a membrane-bound enzyme that regulates bioavailability of multiple transmembrane proteins by proteolytic processing. ADAM17 has been linked to a number of pathologies, but its role in thoracic aortic aneurysm (TAA) has not been determined.
Objective: To explore the cell-specific functions of vascular ADAM17 in the pathogenesis and progression of TAA.
Methods and Results: In aneurysmal thoracic aorta from patients, ADAM17 was increased in tunica media and intima. To determine the function of ADAM17 in the major cells types within these regions, we generated mice lacking ADAM17 in smooth muscle cells (SMC) (Adam17f/f/Sm22Cre/+) or endothelial cells (EC) (Adam17f/f/Tie2Cre/+). ADAM17 deficiency in either cell type was sufficient to suppress TAA dilation markedly and adverse remodeling in males and females (in vivo), although through different mechanisms. ADAM17-deficiency in SMCs prevented the contractile-to-synthetic phenotypic switching in these cells following TAA induction, preventing perivascular fibrosis, inflammation, and adverse aortic remodeling. Loss of ADAM17 in ECs protected the integrity of the intimal barrier by preserving the adherens junction (vascular endothelial cadherin) and tight junctions (junctional adhesion molecule-A and claudin). In vitro studies on primary mouse thoracic SMCs, and human primary SMCs and ECs (± ADAM17 siRNA) confirmed the cell-specific functions of ADAM17 and demonstrated the cross-species validity of these findings. To determine the impact of ADAM17 inhibition in treating TAA, we used an ADAM17-selective inhibitor (PF-548) before, or 3 days after TAA induction. In both cases, ADAM17 inhibition prevented progression of aneurysmal growth.
Conclusions: We have identified distinct cell-specific functions of ADAM17 in TAA progression, promoting pathological remodeling of SMC and impairing integrity of the intimal EC barrier. The dual impact of ADAM17 deficiency (or inhibition) in protecting two major cell types in the aortic wall highlights the unique position of this proteinase as a critical treatment target for TAA.
- A disintegrin and metalloproteinase
- thoracic aortic aneurysm
- smooth muscle cell
- endothelial cell
- animal model of human disease remodeling
- aortic disease
- vascular biology
- vascular smooth muscle
- Received April 5, 2018.
- Revision received June 3, 2018.
- Accepted June 20, 2018.