Reduced versican cleavage due to Adamts9 haploinsufficiency is associated with cardiac and aortic anomalies.
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.
Kern
Christine B
CB
Department of Regenerative Medicine and Cell Biology, 171 Ashley Avenue, Medical University of South Carolina, Charleston, SC 29425, USA. kernc@musc.edu <kernc@musc.edu>
Wessels
Andy
A
McGarity
Jessica
J
Dixon
Laura J
LJ
Alston
Ebony
E
Argraves
W Scott
WS
Geeting
Danielle
D
Nelson
Courtney M
CM
Menick
Donald R
DR
Apte
Suneel S
SS
D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001808:Blood Vessels / Q000378:metabolism; D002319:Cardiovascular System / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism; D005796:Genes; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism; D007763:Lac Operon; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D053675:Versicans / Q000378:metabolism*
D053675:Versicans; D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; C412869:ADAMTS9 protein, human