Reduced endothelin-1 (ET-1) and elevated nitric oxide metabolites (NOX) across pregnancy among andean vs. european women at high (3100-3600 m) altitude

Abstract

Background: A consistent reduction in infant birth weight occurs with ascending altitude; however multigenerational high-altitude residents [Andeans] demonstrate a degree of protection from altitude-associated IUGR relative to their European HA counterparts. This difference has been attributed, in part, to greater uterine artery [UA] enlargement during pregnancy among Andeans. Objective: We asked whether maternal circulating levels of vasoactive and angiogenic proteins regulated by the hypoxia inducible factors [HIF] differed between multi-generational Andean HA residents vs. short-term HA and low-altitude [LA] Europeans. Methods: Serum or plasma was collected from women residing at LA (1610m, Denver, Colorado) and HA (3100 and 3600m, Leadville, CO and La Paz, Bolivia) altitude at 20, 30 and 36w gestation and 3 mo post-partum for a nonpregnant measure. ET-1, placental-like growth factor [PLGF], vascular endothelial growth factor [VEGF-free] and soluble Flt-1 [sFlt-1] were assessed via ELISA [R&D, UK]; NOx was measured using chemiluminescence [Sievers, CO]. Effects of pregnancy, altitude and ancestry were quantified using repeated measures and 2-way ANOVA. Results: Circulating levels of the vasoconstrictor ET-1 declined during pregnancy in both Europeans at LA and Andeans at HA; however at HA ET-1 increased during gestation among Europeans but not Andeans [pregnancy: p 0.05; altitude: p 0.05 and ancestry: p 0.05]. NOx declined across pregnancy in all groups [pregnancy: p 0.05]. Altitude decreased circulating NOx levels among Europeans [altitude: p 0.01]. Andeans at HA demonstrated higher NOx levels relative to Europeans at HA [ancestry: p 0.001]. With pregnancy, VEGF declined and sFlt-1and PLGF increased among all groups [p 0.001], but neither altitude nor ancestry influenced their maternal circulating levels. Conclusions: Protection from IUGR and greater UA enlargement during pregnancy among multi-generational HA residents may be due, in part, to reduced production of the vasoconstrictor ET-1 and/or increased production of the vasodilator NO.