ADAMTS5 Orchestrates Cell Lineage Specific Patterning and Extracellular Matrix Organization During Semilunar Valve Development
Year: 2025
Type: article
Abstract: Aortic valve (AV) disease affects about 5% of the aging population, with AV replacement as the only treatment option. Histopathology indicates that accumulation of extracellular matrix (ECM) proteoglycans correlates with dysfunctional AVs. Proteoglycan content is controlled by ECM proteolytic cleavage, with the cleaved and intact forms of the proteoglycan Versican (VCAN) occupying different cell lineage-specific regions throughout AV development. To test the hypothesis that VCAN cleavage is required for lineage specific cell behaviors and ECM stratification, the cardiac neural crest (CNC) lineage was traced in mice with global inactivation of the proteoglycan protease Adamts5. By mid-gestation, Adamts5−/− mice exhibited disorganized CNC patterning with excess VCAN and enlarged semilunar valve (SLV) morphology. Use of the Adamts5 floxed mice indicated that Adamts5 was required in the endothelial cells and their mesenchymal derivatives (EndoMT lineage) to prevent VCAN accumulation, initiate ECM stratification, and promote normal SLV morphology. These data suggest that the ECM remodeling event of VCAN cleavage may orchestrate cell lineage distinct behaviors and interactions to control proteoglycan levels throughout AV development and to prevent disease. Understanding mechanisms that regulate VCAN content may lead to the discovery of effective pharmacological targets for the treatment of AV disease.
DOI: 10.3390/jcdd12090371
Authors: Loren E. Dupuis, Joshua J. Mifflin, Amy L. Marston, Jeremy P. Laxner, Christine B. Kern
Institution: Medical University of South Carolina
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,258
OpenAlex ID: W4414349740
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