Gestational intermittent hypoxia programs pregnancy-specific salt-sensitive postpartum hypertension and vascular dysfunction via disruption of NO/cGMP/PKG pathway

Obstructive sleep apnea (OSA), common in pregnancy, is linked to preeclampsia and long-term maternal hypertension, but the underlying mechanisms remain unclear. We hypothesized that intermittent hypoxia (IH), a core feature of OSA, primes the maternal vasculature for heightened responses to hypertensive stressors postpartum. Pregnant Sprague-Dawley rats were exposed to either room air or gestational IH from gestational days 10-21. Two months after delivery, all dams were subjected to a high-salt challenge (2% NaCl in drinking water). Blood pressure and heart rate were measured during gestation and before and following salt loading. Vascular function and protein expression were analyzed in mesenteric arteries at study completion. A parallel group of nonpregnant rats underwent identical IH and salt exposure to delineate pregnancy-specific effects. IH exposure in pregnancy led to gestational hypertension that resolved postpartum, whereas nonpregnant rats showed no blood pressure changes. However, following high-salt challenge, postpartum IH-exposed dams displayed significantly greater increases in blood pressure and heart rate, abnormalities not seen in nonpregnant counterparts. Ex vivo, arteries from IH-exposed dams showed enhanced vasocontraction to phenylephrine and impaired vasodilation to both acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent). Molecular analysis revealed increased endothelial nitric oxide synthase activation and decreased protein kinase G (PKG) in the IH group, with no change in α1-adrenergic receptor expression, indicating disrupted vascular smooth muscle signaling. Virgin rats showed no such alterations. Gestational IH induces a pregnancy-specific predisposition to postpartum salt-sensitive hypertension and vascular dysfunction, driven by disrupted PKG signaling. Early OSA detection and intervention in pregnancy may reduce cardiovascular risk.