Patent ductus arteriosus in mice with smooth muscle-specific Jag1 deletion
Xuesong Feng1, Luke T Krebs, Thomas Gridley
1The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Insights
Jag1 signaling is crucial for ductus arteriosus closure in mice. Its absence causes patent ductus arteriosus due to impaired smooth muscle cell differentiation and signaling, highlighting Notch ligand roles in congenital heart defects.
Area of Science:
- Developmental Biology
- Cardiovascular Research
- Genetics
Background:
- The ductus arteriosus is a fetal artery that normally closes after birth.
- Patent ductus arteriosus (PDA) is a common congenital heart defect resulting from failure of ductus arteriosus closure.
- Jagged1 (Jag1) encodes a Notch ligand involved in cell signaling pathways.
Purpose of the Study:
- To investigate the role of Jag1 in smooth muscle cell differentiation and ductus arteriosus closure.
- To elucidate the signaling mechanisms underlying PDA development in a genetic mouse model.
Main Methods:
- Generation of mice with smooth muscle cell-specific deletion of Jag1.
- Analysis of ductus arteriosus morphology, smooth muscle cell differentiation, and Notch signaling.
- Evaluation of endothelial-smooth muscle cell and smooth muscle cell-smooth muscle cell interactions.
Main Results:
- Jag1 deletion in smooth muscle cells leads to postnatal lethality due to PDA.
- Defects in contractile smooth muscle cell differentiation were observed in the ductus arteriosus and descending aorta.
- Impaired lateral induction of JAG1-Notch signaling throughout the vascular wall was identified as a key defect.
Conclusions:
- Jag1-mediated Notch signaling is essential for proper ductus arteriosus development and closure.
- Both heterotypic and homotypic cell interactions involving vascular smooth muscle cells are critical for ductus arteriosus patterning.
- This study presents a novel mouse model for PDA, offering insights into its genetic basis.
Abstract:
The ductus arteriosus is an arterial vessel that shunts blood flow away from the lungs during fetal life, but normally occludes after birth to establish the adult circulation pattern. Failure of the ductus arteriosus to close after birth is termed patent ductus arteriosus and is one of the most common congenital heart defects. Mice with smooth muscle cell-specific deletion of Jag1, which encodes a Notch ligand, die postnatally from patent ductus arteriosus. These mice exhibit defects in contractile smooth muscle cell differentiation in the vascular wall of the ductus arteriosus and adjacent descending aorta. These defects arise through an inability to propagate the JAG1-Notch signal via lateral induction throughout the width of the vascular wall. Both heterotypic endothelial smooth muscle cell interactions and homotypic vascular smooth muscle cell interactions are required for normal patterning and differentiation of the ductus arteriosus and adjacent descending aorta. This new model for a common congenital heart defect provides novel insights into the genetic programs that underlie ductus arteriosus development and closure.
