Endocardial XXXX disruption illustrates the developmental origins of semilunar valve disease.

@entity4503 @entity51418 @entity19 @entity245 @entity19021 @entity361 @entity70693
UNASSIGNED: The formation of intricately organized aortic and pulmonic valves from primitive endocardial cushions of the outflow tract is a remarkable accomplishment of embryonic development. While not always initially pathologic, @entity245 , including @entity4503 , frequently progress to a disease state in adults requiring valve replacement surgery. Disrupted embryonic growth, differentiation, and patterning events that "trigger" SLV disease are coordinated by gene expression changes in endocardial, myocardial, and cushion mesenchymal cells. We explored roles of chromatin regulation in valve gene regulatory networks by conditional inactivation of the @entity70693 ( @entity70693 ) chromatin remodeling complex in the endocardial lineage. Endocardial @entity51418 -deficient @entity19 embryos develop thickened and disorganized SLV cusps that frequently become bicuspid and @entity19021 , including in surviving adults. These SLV disease-like phenotypes originate from @entity361 (EMT) in the proximal outflow tract (pOFT) cushions. The missing cells are replaced by compensating neural crest or other non-EMT-derived mesenchyme. However, these cells are incompetent to fully pattern the valve interstitium into distinct regions with specialized extracellular matrices. Transcriptomics reveal genes that may promote growth and patterning of SLVs and/or serve as disease-state biomarkers. Mechanistic studies of SLV disease genes should distinguish between disease origins and progression; the latter may reflect secondary responses to a disrupted developmental system.
