Oxidative and Inflammatory Mechanisms Induced by Intermittent Hypoxia Leading to Vascular Alterations in Rodents: A Systematic Review and Meta-Analysis.

Objectives: Obstructive sleep apnea (OSA) and the related intermittent hypoxia (IH) are recognized as major cardiovascular risk factors. In a previous meta-analysis, we confirmed the impact of IH on structural and functional remodeling of vessels in rodent models of IH. Here, we conducted a systematic review and meta-analysis to investigate the molecular mechanisms related to vascular remodeling induced by IH and to analyze the impacts of patterns of exposure on the effect of IH. Methods: We searched PubMed, Web of Science, and EMBASE and included 52 articles, among them 44 concerning wild type (WT) rodents and eight concerning apolipoprotein E knockout (ApoE-/-) mice. We used standardized mean difference (SMD) to compare results between studies. A hypoxic score was designed and calculated, and metaregressions were performed to explore the impact of IH exposure parameters on the selected outcomes. Results: IH induced an increase in oxidative stress, inflammation markers, leucocyte infiltration, and apoptosis, and a decrease in endothelial nitric oxide synthase (eNOS) expression and activity in arteries of WT mice. In metaregressions, inflammation and oxidative stress markers were associated with total duration of IH exposure, and eNOS was associated with hypoxic score. In ApoE-/- mice, inflammation markers were significantly increased in atherosclerotic plaques, but leukocyte infiltration and oxidative stress were not modified by IH. Rodent characteristics had only few impacts on the outcomes. Conclusions: Our meta-analysis confirms that IH, independently of measured confounders, has a major impact on oxido-inflammatory mechanisms in vessels, and that the duration of IH can modulate these effects. Our findings strengthen our understanding of molecular mechanisms associated with vascular alterations in IH/OSA.