Mitochondrial contributions to impaired vascular function in healthy young adults exposed to adverse childhood experiences

Introduction: Adverse childhood experiences (ACEs) represent severe psychosocial stressors that increase later-life cardiovascular disease (CVD) risk in a dose-dependent manner. We previously reported that young adults with ACE exposure exhibit impaired vascular endothelial function (VEF), characterized by reduced endothelium-dependent dilation. Excess reactive oxygen species (ROS) and mitochondrial dysfunction contribute to VEF, but whether these factors contribute to ACE-related VEF impairments remain unclear. Therefore, we sought to determine whether ROS and mitochondrial dysfunction contribute to impaired VEF in young adults with ACEs. Methods: VEF was assessed using brachial artery flow-mediated dilation in two separate cohorts. Cohort 1 included 23 young adults (age 24±5 y; BMI 26±5 kg/m 2 ) with (≥3, ACE+; n=12) or without (ACE–; n=11) prior ACE exposure. Human aortic endothelial cells (HAECs) were cultured with 10% participant serum and ROS bioactivity (CellROX) and acetylcholine-stimulated nitric oxide (NO) production (DAR-4M-AM) were quantified. To identify circulating factors contributing to serum exposure-driven differences in HAECs, untargeted metabolomics and targeted proteomics were performed in a representative sub-sample (ACE+, n=7; ACE–, n=7). Cohort 2 included 17 (age 23±3 y; BMI 22±4 kg/m 2 ; ACE+, n=9; ACE–, n=8) participants. HAECs cultured with 10% plasma were assayed for mitochondrial ROS (MitoSOX), respiratory activity (MitoTracker Deep Red), and mitochondrial content (MitoTracker Green). Cellular respiration experiments were performed in peripheral blood mononuclear cells (PBMCs). Results: In both cohorts VEF was lower in ACE+ than ACE– (–3.4±1.2%, p=0.009 and –4.2±1.3%, p=0.007). In Cohort 1, HAECs exposed to serum from those with ACEs exhibited lower ROS bioactivity (1285±121 vs. 1416±127 AU, p=0.019) and 40% lower NO production (p=0.11). Interestingly, ROS bioactivity was positively, but not significantly, associated with VEF (ρ=0.51, p=0.07). Differentially expressed metabolites included higher lysophosphatidylcholine 20:5 (LysoPC; +61%, p=0.033) and lower lysophosphatidic acid 18:1 (LysoPA; –34%, p=0.033) in ACE+, which was accompanied by 45% lower circulating autotaxin (p=0.17). LysoPC and LysoPA were differentially associated with ex vivo ROS (LysoPC: ρ=–0.52, p=0.06; LysoPA: ρ=0.60, p=0.025) and in vivo VEF (LysoPC: ρ=–0.56, p=0.038; LysoPA: ρ=0.49, p=0.08). In Cohort 2, HAECs exposed to plasma from ACE+ exhibited 22% lower respiratory activity (p=0.045), but normalized mtROS bioactivity did not differ (–13%, p=0.29). PBMC mitochondrial parameters, including basal respiration, maximal respiration, and spare respiratory capacity, also did not differ (all p≥0.36). However, normalized mtROS (ACE exposure ´ mtROS interaction: B=3.2±0.9, p< 0.001) and PBMC spare respiratory capacity (B=0.97±0.47, p=0.037) moderated the effect of ACE exposure on VEF, driven by positive associations between VEF and mtROS (r=0.69, p=0.019) and spare capacity (r=0.64, p=0.032) among ACE+. Conclusion: Young adults with prior ACE exposure exhibit impaired VEF alongside counterintuitive effects of the circulating milieu on endothelial ROS generation and mitochondrial respiratory activity, likely tied to altered lipid-related metabolic regulation. The observed moderating effects of spare respiratory capacity and mtROS bioactivity suggest that ACEs recalibrate mitochondrial-redox coupling in a manner that compromises VEF. Together, these findings suggest that early-life adversity disrupts coordinated metabolic, redox, and vascular endothelial pathways that embed long-term cardiovascular vulnerability. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.