Greater aortic stiffness with exposure to early life stress is mediated by oxidant sensitive aortic macrophage population

Childhood abuse ranging from emotional neglect, physical abuse, and household dysfunction describes the term Early Life Stress (ELS). Many studies with human adults exposed to ELS show an elevated risk of cardiovascular disease. Aortic stiffness is a common predictor of future cardiovascular disease risk. Further, previous reports show that adult humans with ELS exposure are associated with higher Pulse Wave Velocity (PWV), a measure of aortic stiffness. Our lab utilizing an established mouse model of ELS, maternal separation with early weaning (MSEW), also found a similar increased PWV in mice exposed to ELS in both sexes. The MSEW protocol is a model of neglect where pups are separated from the dam 4h/day (postnatal, PD 2 to 5) and 8h/day (PD 6 to 16) followed by weaning at PD17. Normally-reared (NR) litters remain with the dam before weaning at PD21. Previous work from our lab showed that mice treated with a reactive oxygen species (ROS) scavenger, TEMPOL (30mg/kg/day; drinking water) from 8 weeks of age restored PWV to that of NR mice in both sexes. Using flow cytometry to assess macrophage populations, we recently found a significant interaction of MSEW and TEMPOL (p=0.005, F=8.99) where TEMPOL only lowered CX3CR1 monocyte expression in MSEW mice (untreated: 6.3 ± 3.67, treated: 2.5 ±1.8 % CD45) compared to NR mice (untreated: 3.99 ± 2.89, treated: 5.77 ± 3.00 %CD45) regardless of sex. Additionally, MSEW mice have elevated plasma Macrophage Colony Stimulating Factor (MCSF-1) at 12 weeks of age (p= 0.01, 945.3 ± 65.41 pg/mL) compared to NR mice (737.4 ± 21.26 pg/mL). Plasma from our human adolescent ESTABLISH cohort also showed significantly elevated MCSF-1 levels in individuals exposed to ELS (ELS: 188.7 ± 15.1 pg/mL, No ELS: 126.2 ± 18.5 pg/mL, p=0.005). We hypothesized that MCSF-1 is required for the development of elevated PWV in MSEW mice compared to NR controls. To test this hypothesis, we utilized anti-MCSF-1 or vehicle (veh) treatment for 2 weeks to prevent macrophage accumulation in the aorta of MSEW mice. After PD 22, mice were treated with anti-MCSF1 or veh. There was an interaction based on MSEW and treatment (p=0.0013, F=14.91) where MSEW mice with veh had elevated PWV (2.5 ± 0.425 m/sec) compared to NR veh controls (1.6 ± 0.28 m/sec). After treatment, MSEW mice had lower PWV (1.52 ± 0.18 m/sec) than MSEW veh in both sexes. PWV in MSEW mice with treatment was not statistically different than untreated and treated NR mice (1.63 ± 0.29 m/sec) in both sexes. In conclusion, reactive oxygen species mediate the elevated aortic stiffness observed in mice exposed to ELS most likely due to the aortic pro-oxidant macrophage population. Monocyte trafficking and maturation driven by MCSF-1 is necessary for ELS-induced elevated aortic stiffness. Future research will focus on structural changes of the aorta after CSF1 treatment and utilize single cell transcriptomics to further understand the macrophage population in the aorta after ELS. This work is instrumental for understanding the mechanism of ELS-induced cardiovascular risk. NIH P01HL158500 F31HL165863-01 This abstract was presented at the American Physiology Summit 2025 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.