APOE-NOTCH axis governs elastogenesis during human cardiac valve remodeling

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Cell Biology

Background:

• Heart valve remodeling involves complex extracellular matrix organization and leaflet elongation.
• Valve interstitial cells (VICs) and valve endothelial cells (VECs) play critical roles in this process.

Purpose of the Study:

• To identify novel cell subtypes and molecular mechanisms regulating elastogenesis in human fetal heart valves.
• To investigate the roles of apolipoprotein E (APOE) and NOTCH signaling in valve remodeling and pulmonary stenosis (PS).

Main Methods:

• Single-cell RNA sequencing of human fetal valves.
• APOE knockdown experiments in fetal VICs.
• Cell-cell interaction analysis and pathway analysis.
• Analysis of gene expression in pulmonary stenosis (PS) valves.

Main Results:

• Identified a novel elastin-producing VIC subtype (APOE+, elastin-VICs) located beneath VECs sensing flow.
• APOE knockdown impaired elastogenesis; PS valves showed elastin fragmentation and reduced APOE expression.
• VEC-derived JAG1 activates elastogenesis in elastin-VICs via NOTCH2, a pathway disrupted in PS.
• APOE regulates JAG1-induced NOTCH activation and elastogenesis through the ERK pathway.

Conclusions:

• APOE and NOTCH signaling are critical regulators of elastogenesis in human valve remodeling.
• Disruption of the JAG1-NOTCH2 pathway and APOE function contributes to valve defects in pulmonary stenosis.
• Elastin-VICs represent a key cell population in maintaining heart valve integrity.