High altitude differentially modulates potassium channel-evoked vasodilatation in pregnant human myometrial arteries

Abstract

High-altitude (>2500 m or 8200 ft) residence reduces uterine artery blood flow during pregnancy, contributing to an increased incidence of preeclampsia and intrauterine growth restriction. However, not all pregnancies are affected by the chronic hypoxic conditions of high-altitude residence. K⁺ channels play important roles in the uterine vascular adaptation to pregnancy, promoting a reduction in myogenic tone and an increase in blood flow. We hypothesized that, in pregnancies with normal fetal growth at high altitude, K⁺ channel-dependent vasodilatation of myometrial arteries is increased compared to those from healthy pregnant women at a lower altitude (∼1700 m). Using pharmacological modulation of two K⁺ channels, ATP-sensitive (K_ATP ) and large-conductance Ca²⁺ -activated (BK_Ca ) K⁺ channels, we assessed the vasodilatation of myometrial arteries from appropriate for gestational age (AGA) pregnancies in women living at high or low altitudes. In addition, we evaluated the localization of these channels in the myometrial arteries using immunofluorescence. Our results showed an endothelium-dependent increase in K_ATP -dependent vasodilatation in myometrial arteries from high versus low altitude, whereas vasodilatation induced by BK_Ca activation was reduced in these vessels. Additionally, K_ATP channel co-localization with endothelial markers was reduced in the high-altitude myometrial arteries, which suggested that the functional increase in K_ATP activity may be by mechanisms other than regulation of channel localization. These observations highlight an important contribution of K⁺ channels to the human uterine vascular adaptation to pregnancy at high altitude serving to maintain normal fetal growth under conditions of chronic hypoxia. KEY POINTS: High-altitude (>2500 m or 8200 ft) residence reduces uterine blood flow during pregnancy and fetal growth. Animal models of high altitude/chronic hypoxia suggest that these reductions are partially due to reduced vascular K^+. channel responses, such as those elicited by large conductance Ca²⁺ -activated (BK_Ca ) and ATP-sensitive (K_ATP ) K⁺ channel activation. We found that women residing at high versus low altitude during pregnancy showed diminished myometrial artery vasodilatory responses to endothelium-independent BK_Ca channel activation but greater responses to endothelium-dependent K_ATP channel activation. Our observations indicate that K_ATP channels play an adaptive role in maintaining myometrial artery vasodilator sensitivity under chronic hypoxic conditions during pregnancy. Thus, K_ATP channels represent potential therapeutic targets for augmenting uteroplacental blood flow and, in turn, preserving fetal growth in cases of uteroplacental hypoperfusion.

Keywords: chronic hypoxia; fetal growth; high altitude; uterine vessels.