Unidirectional Shear Stress-Operated NOTCH/CXCR4 Molecular Switch Controls Semilunar Valve Maturation and Collagen...

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Molecular Cardiology

Background:

• Mechanisms of fetal heart valve remodeling are not fully understood.
• The role of hemodynamic forces in valvulogenic signaling during development is unclear.
• Hypothesized that shear stress-specific endocardial signaling directs valve leaflet remodeling and maturation.

Purpose of the Study:

• To investigate how local hemodynamic stress regulates the maturation of fetal semilunar heart valves.
• To determine the interaction between hemodynamic forces and valvulogenic signaling programs.

Main Methods:

• Identified ventricularis-specific expression of endocardial NOTCH1 and mesenchymal CXCR4.
• Generated conditional Notch and Cxcr4 mouse deletions for in vivo analysis.
• Utilized ex vivo chick endocardial cells and valve organoids for gain and loss of function studies.
• Performed quantitative analysis via histology, immunohistochemistry, and qRT-PCR.

Main Results:

• Unidirectional laminar shear stress regulates CXCR4 via endocardial NOTCH signaling, upregulating SDF1.
• Global and mesenchymal-specific Cxcr4 deletion led to hyperproliferative and thickened outflow tract valves.
• Cxcr4 ablation inhibited BMP and WNT signaling, promoting matrix remodeling and tissue compaction.

Conclusions:

• High-magnitude unidirectional laminar shear stress activates a NOTCH1/CXCR4 molecular switch in endocardial cells.
• This switch inhibits valve mesenchymal growth while promoting condensation, differentiation, and ECM remodeling.
• Identified a novel hemodynamic-controlled molecular switch directing side-specific valve maturation.