Obstructive sleep apnea (OSA) is an independent risk factor for the development of vascular disease. OSA is characterized by upper airway collapse during sleep resulting in intermittent periods of hypoxemia and sleep disruption. We hypothesized that OSA-associated chronic intermittent hypoxia (CIH) increases vascular reactive oxygen species production and thereby reduces nitric oxide (NO) bioavailability. We tested this hypothesis by developing a mouse model of CIH that mimics a frequency of oxyhemoglobin desaturations common in severe OSA. Male wild-type C57Bl/6 mice, aged 8-10 weeks, were exposed to an 8-hour protocol of CIH 5 days per week for 8 weeks. Mice were exposed to hypoxia every 40-45 seconds generating a 30-second nadir of 10% O2 mimicking a respiratory disturbance index of 48. Male Sprague-Dawley rats exposed to this CIH protocol demonstrated an average oxyhemoglobin nadir of 80 6 5% as measured with tail pulse oximetry. After 8 weeks mice were sacrificed. Compared to controls (C), CIH mice demonstrated reduced nitrosyl-hemoglobin values, an index of bioavailable NO detected with electron spin resonance spectroscopy (CIH = 855 6 23 vs C = 723 6 45 AU, p = .048). Although there was no difference in body weight between (C) and CIH mice, heart weight was higher in CIH mice compared to (C) mice (CIH = 154 6 6 mg vs C = 125 6 4 mg, p = .004). CIH mice demonstrated evidence of pulmonary hypertension (RV systolic pressure; CIH = 32.4 6 1.3 vs C = 25.7 6 1.6 mm Hg, p = .002) and right ventricular enlargement (RV weight; CIH = 27.7 6 2.6 vs C = 20.4 6 1.0 mg, p = .018). These preliminary findings of pulmonary hypertension and right ventricular hypertrophy validate a new pattern of CIH simulating severe OSA typically seen in sleep apnea patients. This model will be useful for examining the molecular pathogenesis of OSA-associated vascular disease.
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