ESPE Abstracts

The condition of being small for gestational age (SGA) poses significant risks to both infant development delay and chronic non-communicable diseases in adultood, especially cardiovascular diseases. Despite the known association between SGA and endothelial dysfunction, the precise pathogenic genes and underlying mechanisms driving this pathology have remained elusive. In this study, we conducted a comprehensive evaluation of endothelial dysfunction in SGA by their increased angiogenesis, migration, proliferation and wound healing capacity, accompanied by significant changes in their global regulatory landscape. Specifically, we observed increased chromatin accessibility at active enhancer sites, along with dysregulation of genes implicated in angiogenesis and adult diseases. Furthermore, we identified CD44 as a pivotal gene driving SGA-HUVECs dysfunction by CD44 interference and overexpression. Mechanistically, we found that CD44 was abnormally up-regulated by three enhancers located on the CD44 gene body, which exhibited increased accessibility and interaction with the CD44 promoter region. Further analysis unveiled the transcription factor AP-1 as a key regulator of elevated CD44 expression, acting through direct binding to both the CD44 promoter and its associated enhancers. Enhancers CRISPRi and AP-1 inhibition restored CD44 expression and mitigated the aberrant angiogenesis in SGA. Collectively, our findings not only shed light on the molecular underpinnings of SGA-associated endothelial dysfunction but also identify potential diagnostic biomarkers and therapeutic targets for fetal originated adult diseases.