The dissection and rupture of aortic aneurysms account for 1-2% of deaths in Western countries. Histological examination of an aneurysmal aorta demonstrates vascular smooth muscle cell (SMC) and extracellular matrix (ECM) disorganization. It is widely accepted that increased levels of matrix metalloproteinases (MMPs) correlate with aneurysms and degeneration of arterial wall tissue. However recent studies from our laboratory indicate that reduced activity of the ECM protease ADAMTS5 results in arterial wall abnormalities. We have discovered that Aggrecan (Acan), a proteoglycan substrate of ADAMTS5 accumulates in the aortic wall of Adamts5-/- mice and is associated with ascending aortic anomalies and SMC loss. Since Acan contributes to the rigid, non-compressible biomaterial property of cartilage, the lack of its rapid proteolytic turnover in the aorta of Adamts5-/- mice may impact the flexibility of this elastic tissue. Although ECM proteases are typically associated with end-stage degenerative diseases our data suggests a novel and critical role for ADAMTS5 in normal development of the aortic artery. Moreover, our studies indicate that ADAMTS5 may play a key role in the interdependence of SMC and ECM to mediate the adaptive ability of arterial tissue in response to changes in biomechanical force. Our overarching hypothesis states that ADAMTS5-mediated proteolytic cleavage and ECM clearance of its substrate Aggrecan is critical for development of the ascending aorta. Aim 1 will determine the requirement of ADAMTS5 proteolytic turnover of its ECM substrate Aggrecan during development of the ascending aortic artery. The consequence of ADAMTS5 deficiency on the smooth muscle cell phenotype and function in the ascending aortic wall will be determined. Given that aortic anomalies are defined by disruption of ECM organization and altered SMC function, yet factors that generate vascular integrity and adaptability remain largely unknown, experiments in this proposal investigate an important aspect of vascular biology. Determining the cleaved Acan fragments in healthy aortic tissue may lead to novel diagnostic markers of aortic wall integrity, plus may identify early stages of disease and improve treatment intervention. We anticipate that data will redefine ECM proteases as critical for ECM assembly giving insight into off-target effects for their pharmacological inhibitors employed to treat degenerative diseases.
|Effective start/end date||07/01/2017 → 06/30/2019|