Cadherin-11 coordinates cellular migration and extracellular matrix remodeling during aortic valve maturation

Dev Biol. 2015 Nov 1;407(1):145-57. doi: 10.1016/j.ydbio.2015.07.012. Epub 2015 Jul 16.


Proper remodeling of the endocardial cushions into thin fibrous valves is essential for gestational progression and long-term function. This process involves dynamic interactions between resident cells and their local environment, much of which is not understood. In this study, we show that deficiency of the cell-cell adhesion protein cadherin-11 (Cad-11) results in significant embryonic and perinatal lethality primarily due to valve related cardiac dysfunction. While endocardial to mesenchymal transformation is not abrogated, mesenchymal cells do not homogeneously cellularize the cushions. These cushions remain thickened with disorganized ECM, resulting in pronounced aortic valve insufficiency. Mice that survive to adulthood maintain thickened and stenotic semilunar valves, but interestingly do not develop calcification. Cad-11 (-/-) aortic valve leaflets contained reduced Sox9 activity, β1 integrin expression, and RhoA-GTP activity, suggesting that remodeling defects are due to improper migration and/or cellular contraction. Cad-11 deletion or siRNA knockdown reduced migration, eliminated collective migration, and impaired 3D matrix compaction by aortic valve interstitial cells (VIC). Cad-11 depleted cells in culture contained few filopodia, stress fibers, or contact inhibited locomotion. Transfection of Cad-11 depleted cells with constitutively active RhoA restored cell phenotypes. Together, these results identify cadherin-11 mediated adhesive signaling for proper remodeling of the embryonic semilunar valves.

Keywords: Aortic valve insufficiency; Calcification; Compaction; Congenital heart defect; Filopodia; Hyperplasia; RhoA; Stress fiber.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aortic Valve / cytology
  • Aortic Valve / embryology*
  • Cadherins / physiology*
  • Cell Movement*
  • Cell Polarity
  • Chickens
  • Endocardial Cushions / embryology
  • Extracellular Matrix / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Morphogenesis
  • Swine
  • rhoA GTP-Binding Protein / physiology


  • Cadherins
  • osteoblast cadherin
  • rhoA GTP-Binding Protein