ADAMTS5 Orchestrates Cell Lineage Specific Patterning and Extracellular Matrix Organization During Semilunar Valve...

Area of Science:

• Cardiovascular Biology
• Extracellular Matrix Biology
• Developmental Biology

Background:

• Aortic valve disease affects 5% of the aging population, with replacement as the sole treatment.
• Dysfunctional aortic valves show increased extracellular matrix (ECM) proteoglycans.
• Versican (VCAN) proteoglycan levels are regulated by ECM proteolytic cleavage.

Purpose of the Study:

• To investigate if Versican (VCAN) cleavage by Adamts5 is essential for cell behaviors and ECM organization during aortic valve development.
• To determine the role of Adamts5 in cardiac neural crest (CNC) and endothelial-mesenchymal transition (EndoMT) lineages during aortic valve formation.

Main Methods:

• Cardiac neural crest (CNC) lineage tracing in mice lacking Adamts5.
• Utilized Adamts5 floxed mice to assess gene function in specific cell types.
• Analyzed Versican accumulation, ECM stratification, and semilunar valve (SLV) morphology.

Main Results:

• Mice lacking Adamts5 displayed disorganized CNC patterning, excess VCAN, and enlarged semilunar valves.
• Adamts5 is required in endothelial cells and their mesenchymal derivatives (EndoMT lineage) to control VCAN levels and ECM stratification.
• Loss of Adamts5 function leads to abnormal aortic valve morphology.

Conclusions:

• VCAN cleavage by Adamts5 is a key ECM remodeling event orchestrating cell behaviors and proteoglycan levels during aortic valve development.
• Understanding VCAN regulation may reveal therapeutic targets for aortic valve disease.
• Adamts5 plays a critical role in maintaining aortic valve structure and function.