Reduced versican cleavage due to Adamts9 haploinsufficiency is associated with cardiac and aortic anomalies

• Published in: Matrix biology Vol. 29; no. 4; pp. 304 - 316
• Main Authors: Kern, Christine B., Wessels, Andy, McGarity, Jessica, Dixon, Laura J., Alston, Ebony, Argraves, W. Scott, Geeting, Danielle, Nelson, Courtney M., Menick, Donald R., Apte, Suneel S.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2010
• Subjects: ADAM Proteins; ADAMTS; ADAMTS9 Protein; Animals; Aorta - metabolism; Blood Vessels - metabolism; Cardiovascular System - metabolism; Embryonic Development - genetics; Embryonic Development - physiology; Extracellular matrix; Extracellular Matrix - metabolism; Genes; Heart - embryology; Heart Defects, Congenital - metabolism; Heart Ventricles - metabolism; Lac Operon; Mesenchymal Stem Cells - metabolism; Mice; Mice, Transgenic; Myocardium - metabolism; Myocytes, Cardiac - metabolism; Myxomatous valves; Versican; Versicans - metabolism; αSMA; Myxomatous valves; ADAMTS; Extracellular matrix; OFT; WT; ECM; Versican
• ISSN: 0945-053X; 1569-1802; 1569-1802
• DOI: 10.1016/j.matbio.2010.01.005

Here, we demonstrate that ADAMTS9, a highly conserved versican-degrading protease, is required for correct cardiovascular development and adult homeostasis. Analysis of Adamts9+/LacZ adult mice revealed anomalies in the aortic wall, valvulosinus and valve leaflets. Abnormal myocardial projections and ‘spongy’ myocardium consistent with non-compaction of the left ventricle were also found in Adamts9+/LacZ mice. During development, Adamts9 was expressed in derivatives of the Secondary Heart Field, vascular smooth muscle cells in the arterial wall, mesenchymal cells of the valves, and non-myocardial cells of the ventricles, but expression also continued in the adult heart and ascending aorta. Thus, the adult cardiovascular anomalies found in Adamts9+/LacZ hearts could result from subtle developmental alterations in extracellular matrix remodeling or defects in adult homeostasis. The valvular and aortic anomalies of Adamts9+/LacZ hearts were associated with accumulation of versican and a decrease in cleaved versican relative to WT littermates. These data suggest a potentially important role for ADAMTS9 cleavage of versican, or other, as yet undefined substrates in development and allostasis of cardiovascular extracellular matrix. In addition, these studies identify ADAMTS9 as a potential candidate gene for congenital cardiac anomalies. Mouse models of ADAMTS9 deficiency may be useful to study myxomatous valve degeneration.