Gestational intermittent hypoxia induces endothelial dysfunction and hypertension in pregnant rats: role of endothelin type B receptor†

Obstructive sleep apnea (OSA) is a recognized risk factor for gestational hypertension, yet the exact mechanism behind this association remains unclear. Here, we tested the hypothesis that intermittent hypoxia (IH), a hallmark of OSA, induces gestational hypertension through perturbed endothelin-1 signaling. Pregnant Sprague-Dawley rats were subjected to normoxia (control), mild IH (mIH, 10.5% O2), or severe IH (sIH, 6.5% O2) from gestational day 10-21. Blood pressure (BP) was monitored. Plasma was collected and mesenteric arteries were isolated for myograph and protein analyses. The mIH and sIH groups demonstrated elevated BP, reduced plasma nitrate/nitrite (NOx), and unchanged endothelin-1 levels compared to the control group. Western blot analysis revealed decreased expression of endothelin type B receptor (ETBR) and phosphorylated endothelial nitric oxide synthase (eNOS), while the levels of endothelin type A receptor (ETAR) and total eNOS remained unchanged following IH exposure. The contractile responses to potassium chloride, phenylephrine, and endothelin-1 were unaffected in endothelium-denuded arteries from mIH and sIH rats. However, mIH and sIH rats exhibited impaired endothelium-dependent vasorelaxation responses to ETBR agonist IRL-1620 and acetylcholine compared to controls. Endothelium denudation abolished IRL-1620-induced vasorelaxation, supporting the involvement of endothelium in ETBR-mediated relaxation. Treatment with IRL-1620 during IH exposure significantly attenuated IH-induced hypertension in pregnant rats. This was associated with elevated circulating NOx levels, enhanced ETBR expression, increased eNOS activation, and improved vasodilation responses. Our data suggested that IH exposure during gestation increases BP in pregnant rats by suppressing ETBR-mediated signaling, providing a molecular mechanism linking IH and gestational hypertension.

blood pressure; eNOS; endothelin type B receptor; endothelium; intermittent hypoxia; pregnancy.