Abstract
Thoracic aortic aneurysm (TAA), a degenerative disease of the aortic wall, is accompanied by changes in the structure and composition of the aortic ECM (extracellular matrix). The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of proteases has recently been implicated in TAA formation. This study aimed to investigate the contribution of ADAMTS-5 to TAA development. A model of aortic dilatation by AngII (angiotensin II) infusion was adopted in mice lacking the catalytic domain of ADAMTS-5 (Adamts5Δcat). Adamts5Δcat mice showed an attenuated rise in blood pressure while displaying increased dilatation of the ascending aorta (AsAo). Interestingly, a proteomic comparison of the aortic ECM from AngII-treated wild-type and Adamts5Δcat mice revealed versican as the most upregulated ECM protein in Adamts5Δcat mice. This was accompanied by a marked reduction of ADAMTS-specific versican cleavage products (versikine) and a decrease of LRP1 (low-density lipoprotein-related protein 1). Silencing LRP1 expression in human aortic smooth muscle cells reduced the expression of ADAMTS5, attenuated the generation of versikine, but increased soluble ADAMTS-1. A similar increase in ADAMTS-1 was observed in aortas of AngII-treated Adamts5Δcat mice but was not sufficient to maintain versican processing and prevent aortic dilatation. Our results support the emerging role of ADAMTS proteases in TAA. ADAMTS-5 rather than ADAMTS-1 is the key protease for versican regulation in murine aortas. Further studies are needed to define the ECM substrates of the different ADAMTS proteases and their contribution to TAA formation.
Highlights
ADAMTS-1, -4, and -5 activities have been implicated in thoracic aortic aneurysm (TAA) formation.[3,7,8]
AngII treatment was associated with increased aortic dilatation in Adamts5Δcat mice (Figure 2A and 2B); significant differences compared with Adamts5+/+ were observed both in the aortic root, in particular in the aortic annulus, and the ascending aorta (AsAo)
We demonstrated that deficiency of ADAMTS-5 affects ADAMTS-1 gene expression, protein abundance and processing and resulted in aortic dilatation similar to the phenotype recently described in Adamts1-haploinsufficient mice.[3]
Summary
An expanded Materials and Methods section is available in the online-only Data Supplement. The data that support the findings of this study are available from the corresponding author on reasonable request. All animal procedures were performed by authorized researchers in the Cardiovascular Division, King’s College London. Animals were euthanized after 4 weeks, and the entire aorta was excised and immediately washed in sterile phosphatebuffered saline. The entire aorta was snap-frozen at −80°C for subsequent proteomic analysis. Aortic tissue was divided into anatomically defined regions using a scalpel under a dissecting microscope, followed by immediate storage at −80°C. Aortic diameter was monitored using ultrasound at day 0 (baseline) and after 27 days of AngII treatment using Vevo software version 1.7
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Arteriosclerosis, Thrombosis, and Vascular Biology
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
