De Novo Elastin Assembly Alleviates Development of Supravalvular Aortic Stenosis

BACKGROUND: A series of incurable cardiovascular disorders arise due to improper formation of elastin during development. Supravalvular aortic stenosis (SVAS), resulting from a haploinsufficiency of ELN , is caused by improper stress sensing by medial vascular smooth muscle cells, leading to progressive luminal occlusion and heart failure. SVAS remains incurable, as current therapies do not address the root issue of defective elastin. METHODS: We use SVAS here as a model of vascular proliferative disease using both human induced pluripotent stem cell–derived vascular smooth muscle cells and developmental Eln +/– mouse models to establish de novo elastin assembly as a new therapeutic intervention. RESULTS: We demonstrate mitigation of vascular proliferative abnormalities following de novo extracellular elastin assembly through the addition of the polyphenol epigallocatechin gallate to SVAS human induced pluripotent stem cell–derived vascular smooth muscle cells and in utero to Eln +/– mice. CONCLUSIONS: We demonstrate de novo elastin deposition normalizes SVAS human induced pluripotent stem cell–derived vascular smooth muscle cell hyperproliferation and rescues hypertension and aortic mechanics in Eln +/– mice, providing critical preclinical findings for the future application of epigallocatechin gallate treatment in humans.