Early Life Stress Mediates Enhanced Aortic Vasorelaxation in Sv129 Mice

Abstract

Early life stress (ELS) is an under‐appreciated risk factor for cardiovascular disease (CVD). In humans, adverse childhood experiences (ACEs) or ELS is recognized as inducing behavioral or emotional stress. We reported that young adults exposed to ACEs display enhanced vascular stiffness, increased peripheral resistance, and elevated plasma ET‐1. We hypothesized that vascular endothelial‐derived ET‐1 is associated with vascular dysfunction after exposure to ELS. We hypothesized that endothelial‐derived ET‐1 is linked to vascular dysfunction in ELS. To test this hypothesis, we utilized vascular endothelial‐specific ET‐1 knockout (VEETKO) and flox control mice exposed to normal rearing (NR) or maternal separation with early weaning (MSEW). Briefly, MSEW involves maternal separation for 4h/day (postnatal (PD) 2 to 5), 8h/day (PD6 to 16), and weaned at PD17. NR litters were weaned at PD21. Male and female adult NR and MSEW, flox control (n=3–5) and VEETKO (n=5) mice were used to study acetylcholine (Ach)‐ and sodium nitroprusside (SNP)‐mediated aortic vasorelaxation. Interestingly, aorta from MSEW flox mice showed significantly greater maximal Ach‐mediated vasorelaxation compared to NR flox mice (Flox‐control 74.7% SEM 4.15, Flox‐MSEW 93.7% SEM 1.63, VEETKO‐control 78.0% SEM 6.81, VEETKO‐MSEW 86.9% SEM 2.05; p=0.0023). EC50 responses to Ach were not significantly different (Flox‐NR −6.22 SEM 0.330, Flox‐MSEW −6.88 SEM 0.124, VEETKO‐NR −6.70 SEM 0.144, VEETKO‐MSEW −6.88 SEM 0.268; p=0.066). All responses to SNP were similar. The VEETKO and flox control mice are on a Sv129 background. We previously reported that C57Bl/6J mice exposed to MSEW displayed endothelial dysfunction when compared to NR. Thus, these data suggest that exposure to MSEW has a different mechanistic response to the MSEW protocol with different strains of mice. Future studies will include behavioral studies to determine whether the MSEW protocol in Sv129 mice is distinct from the pro‐anxiety response reported in C57Bl/6J mice.Support or Funding InformationFunding K01‐DK‐105038 KAH, RO1 HL136936 JSP and DMPPROmoTE R25 DK 112731