| First Author | Dupuis LE | Year | 2019 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 39 |
| Issue | 10 | Pages | 2067-2081 |
| PubMed ID | 31366218 | Mgi Jnum | J:306256 |
| Mgi Id | MGI:6709674 | Doi | 10.1161/ATVBAHA.119.313077 |
| Citation | Dupuis LE, et al. (2019) Adamts5(-/-) Mice Exhibit Altered Aggrecan Proteolytic Profiles That Correlate With Ascending Aortic Anomalies. Arterioscler Thromb Vasc Biol 39(10):2067-2081 |
| abstractText | 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 than Adamts5(-/-);Smad2(+/-) mice with tricuspid aortic valves. Single mutant Adamts5(-/-) 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 in Adamts5(-/-) 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 the Adamts5(-/-) aortas compared with WT. Conversely, neo-TEGE, which recognizes highly digested Acan core fragments, was reduced in Adamts5(-/-) mice. However, mice containing a mutation in the TEGE373 downward arrow374ALGSV 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 in Adamts5(-/-) 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. |
