Adverse Childhood Experience-conditioned serum from young adults promotes a dysregulated endothelial cell gene expression profile

Abstract

INTRODUCTION AND OBJECTIVES: Adverse Childhood Experiences (ACEs) are some of the most intensive and frequently occurring sources of stress that children may suffer in early life. There events are known to cause health problems across the life course leading to earlier mortality. In particular, ACEs have been associated with an increased risk of developing cardiovascular disease (CVD) in adulthood, although the mechanisms leading to these outcomes remain poorly understood. Endothelial dysfunction is one of the earliest signs of cardiac pathology and can establish long-term changes in inflammatory state, blood composition, and vasomotor activity. The objective of this study was to investigate gene expression changes in primary endothelial cells when exposed to serum of those who have experienced ACEs (0 vs. ≥4). METHODS: Serum samples came from the Niagara Longitudinal Heart Study (NLHS). Samples collected from young male participants were divided into groups based on their ACE exposure (0 ACEs and ≥4 ACEs), with 20 samples investigated for each group. The blood serum was then added to near-confluent male human coronary artery endothelial cells (HCAEC) for various lengths of time (0, 1, 4, 24 hours). The mRNA from these cells were collected and an amplification efficiency-optimized qPCR design was used to determine expression changes for a panel of genes linked to endothelial dysfunction. RESULTS: When exposed to serum from the high ACEs group, the endothelial cells had significantly higher expression of Intercellular Adhesion Molecule 1 (ICAM1) (p<0.001), Chemokine Ligand 2 (CCL2) (p=0.02), Vascular Cell Adhesion Molecule 1 (VCAM1) (p<0.001), and Endothelin-1 (EDN1) (p<0.01) and lower expression of Nitric Oxide Synthase 3 (NOS3) (p=0.048) than the cells that were exposed to serum from the zero ACEs group. CONCLUSION: Overall, higher expression of inflammatory mediators (ICAM1, CCL2, VCAM1), as well as decreased expression of the vasodilator NOS3 and increased expression of the vasoconstrictor EDN1 points to an endothelial transcriptional profile in which high ACEs promote circulating blood conditions in young adulthood that indicate endothelial dysfunction. This suggests that dysfunction of the endothelium may be an early mechanism through which ACEs can lead to increased risk for poor CVD trajectories across the life course.