Early life stress induces circulating factor(s) promoting endothelial dysfunction (1085.3)

Abstract

In humans, early life stress (ELS) increases cardiovascular disease (CVD) risk and elevates circulating pro‐oxidant factors; however the relationship between ELS‐induced CVD and circulating pro‐oxidant factors is not known. In a mouse model of ELS, maternal separation with early weaning (MSEW), we previously showed that MSEW induces adult endothelial dysfunction. We hypothesized that MSEW promotes endothelial dysfunction by increasing circulating factors that increase superoxide (O2‐) production and reduce NO bioavailability in endothelial cells. MSEW litters underwent maternal separation during postnatal days (PD) 2‐16 for 4‐8h/day, and weaning at PD17. Control (CON) litters remained undisturbed and were weaned at PD21. To determine the impact of MSEW‐induced circulating factors on endothelial function, we incubated Mouse Aortic Endothelial Cells (MAECs) with plasma of CON or MSEW mice (25 ul plasma/ml media; 24 hr). MSEW plasma‐treated MAECs had increased O2‐ levels compared to CON (dihydroethidium‐HPLC; CON = 25.7 + 9.7 vs MSEW = 107.0 + 18.5 pmol/mg pr/hr; p < 0.001). Apocynin (300 μM; NADPH oxidase inhibitor) abolished this effect. However, no change in NO bioavailability (nitrite determination by HPLC) was found. In conclusion, MSEW may promote cardiovascular disease risk by inducing circulating factors that enhance endothelial O2‐ production in an NADPH oxidase‐dependent manner.Grant Funding Source: Supported by NIH grants 1F32 HL116145; P01 HL69999