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Objective: Investigate the requirement of Aggrecan (Acan) cleavage during aortic wall development in a murine model with ADAMTS (a disintegrin-like and metalloprotease domain with thrombospondin-type motifs) 5 deficiency and bicuspid aortic valves. Approach: Mice with altered extracellular matrix remodeling of proteoglycans will be examined for anomalies in ascending aortic wall development. Neo-epitope antibodies that recognize ADAMTS cleaved Acan fragments will be used to investigate the mechanistic requirement of Acan turnover, in aortic wall development. Results: Adamts5 −/− ;Smad2 +/− mice exhibited a high penetrance of aortic anomalies (n=17/17);Adamts5 −/− ;Smad2 +/− mice with bicuspid aortic valves (7/17) showed a higher number of anomalies thanAdamts5 −/− ;Smad2 +/− mice with tricuspid aortic valves. Single mutantAdamts5 −/− mice also displayed a high penetrance of aortic anomalies (n=19/19) compared with wild type (n=1/11). Aortic anomalies correlated with Acan accumulation that was apparent at the onset of elastogenesis inAdamts5 −/− mice. Neo-epitope antibodies that recognize the initial amino acids in the Acan cleaved fragments neo-FREEE, neo-GLGS, and neo-SSELE were increased in theAdamts5 −/− aortas compared with WT. Conversely, neo-TEGE, which recognizes highly digested Acan core fragments, was reduced inAdamts5 −/− mice. However, mice containing a mutation in the TEGE373 ↓374 ALGSV site, rendering it noncleavable, had low penetrance of aortic anomalies (n=2/4). Acan neo-DIPEN and neo-FFGVG fragments were observed in the aortic adventitia; Acan neo-FFGVG was increased abnormally in the medial layer and overlapped with smooth muscle cell loss inAdamts5 −/− aortas.Conclusions: Disruption of ADAMTS5 Acan cleavage during development correlates with ascending aortic anomalies. These data indicate that the mechanism of ADAMTS5 Acan cleavage may be critical for normal aortic wall development.

Adamts5 −/− Mice Exhibit Altered Aggrecan Proteolytic Profiles That Correlate With Ascending Aortic Anomalies

Adamts5 ^−/− Mice Exhibit Altered Aggrecan Proteolytic Profiles That Correlate With Ascending Aortic Anomalies