Dupuis Loren E, Mifflin Joshua J, Marston Amy L, Laxner Jeremy P, Kern Christine B
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
J Cardiovasc Dev Dis. 2025 Sep 19;12(9):371. doi: 10.3390/jcdd12090371.
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 . By mid-gestation, mice exhibited disorganized CNC patterning with excess VCAN and enlarged semilunar valve (SLV) morphology. Use of the floxed mice indicated that 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.
主动脉瓣（AV）疾病影响着约5%的老年人群，主动脉瓣置换是唯一的治疗选择。组织病理学表明，细胞外基质（ECM）蛋白聚糖的积累与功能失调的主动脉瓣相关。蛋白聚糖含量受ECM蛋白水解切割控制，蛋白聚糖多功能蛋白聚糖（VCAN）的切割形式和完整形式在整个主动脉瓣发育过程中占据不同的细胞谱系特异性区域。为了验证VCAN切割对于谱系特异性细胞行为和ECM分层是必需的这一假设，在蛋白聚糖蛋白酶全局失活的小鼠中追踪心脏神经嵴（CNC）谱系。到妊娠中期，小鼠表现出紊乱的CNC模式，伴有过量的VCAN和扩大的半月瓣（SLV）形态。使用floxed小鼠表明，在内皮细胞及其间充质衍生物（内皮-间充质转化谱系）中需要[具体蛋白酶名称缺失]来防止VCAN积累、启动ECM分层并促进正常的SLV形态。这些数据表明，VCAN切割的ECM重塑事件可能协调细胞谱系不同的行为和相互作用，以控制整个主动脉瓣发育过程中的蛋白聚糖水平并预防疾病。了解调节VCAN含量的机制可能会发现治疗主动脉瓣疾病的有效药理学靶点。
