A SOX17-PDGFB signaling axis regulates aortic root development

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Genetics

Background:

• Congenital aortic root abnormalities, including bicuspid aortic valves and anomalous coronary arteries, have unknown developmental origins.
• Understanding the genetic and molecular mechanisms is crucial for addressing these complex heart defects.

Purpose of the Study:

• To investigate the role of Sox17 in the development of the aortic root and associated structures.
• To elucidate the molecular pathways involved in Sox17-mediated aortic root patterning.

Main Methods:

• Utilized a mouse model with targeted deletion of the Sox17 gene in aortic root endothelium.
• Analyzed aortic root morphology, valve formation, and coronary ostium positioning.
• Investigated gene expression, specifically focusing on Pdgfb and PDGFB signaling pathways.
• Performed rescue experiments by restoring PDGFB expression.

Main Results:

• Sox17 deletion resulted in an underdeveloped aortic root, absence of the non-coronary leaflet, and a mispositioned left coronary ostium.
• These defects were linked to reduced proliferation of mesenchyme and smooth muscle cells derived from the second heart field.
• Sox17 was found to regulate Pdgfb transcription via an enhancer element, inhibiting endothelial Pdgfb expression and downstream PDGFB signaling.
• Restoration of PDGFB in the aortic root endothelium rescued the observed developmental defects.

Conclusions:

• A SOX17-PDGFB signaling axis is critical for normal aortic root development, including aortic valve and coronary ostium patterning.
• This pathway may represent a shared mechanism underlying concurrent anomalous aortic valve and coronary artery diseases.
• Findings provide insights into the etiology of complex congenital heart abnormalities.