Intermittent hypoxia-related alterations in vascular structure and function: a systematic review and meta-analysis of rodent data

Abstract

Obstructive Sleep Apnea and the related intermittent hypoxia (IH) are widely recognised as risk factors for incident cardiovascular diseases. Numerous studies support the deleterious vascular impact of IH in rodents but an overall interpretation is challenging owing to heterogeneity in rodent species investigated and the severity and duration of IH exposure.To clarify this major issue, we conducted a systematic review and meta-analysis to quantify the impact of IH on systemic artery structure and function depending on the different IH exposure designs.We searched PubMed, Embase and Web of Sciences and included 125 articles in a meta-analysis, among them 112 using wild-type rodents and 13 using Apolipoprotein E knock-out mice. We used the standardised mean difference (SMD) to compare results between studies.IH significantly increased mean arterial pressure (+13.90 mmHg (95% CI [11.88; 15.92]), systolic and diastolic blood pressure. Meta-regressions showed that mean arterial pressure change was associated with strain and year of publication. IH altered vasodilation in males but not in females, and increased endothelin-1-induced, but not phenylephrine-induced, vasoconstriction. Intima-media thickness significantly increased upon IH exposure (SMD 1.10 [0.58; 1.62], absolute values: +5.23 (2.81–7.84)). This increase was observed in mice but not in rats, and was negatively associated with age. Finally IH increased atherosclerotic plaque size in ApoE−/− mice (SMD 1.08 [0.80; 1.37]).To conclude, our meta-analysis established that IH, independently of other confounders, has a strong effect on vascular structure and physiology. Our findings support the interest of identifying and treating sleep apnea in routine cardiology practice.

Cardiac consequences of intermittent hypoxia: a matter of dose? A systematic review and meta-analysis in rodents

“…We confirmed our recent meta-analysis on the vascular impact of IH [ 24 ] and demonstrated that IH induces a significant increase in MAP (SMD=1.19; CI (0.85–1.52); I 2 =68.5%) ( figure 4a ) and HR (SMD=0.34; CI (0.06–0.62); I 2 =48.9%) ( figure 4b ). Most importantly, IH significantly reduces EF (SMD=−1.82; CI (−2.52–−1.12); I 2 =94.2%) ( figure 4c ).…”

“…Differences in population characteristics (animal species, strain, age, sex, body weight), IH protocols and a lack of precision regarding period of IH exposure (during sleep or wakefulness) can explain a part of this heterogeneity, while multivariate meta-regressions showed inconsistent results among studied outcomes and should be interpreted cautiously due to the limited number of studies in some subgroups. For example, as similarly reported in our recent meta-analysis investigating the vascular impact of IH in rodents [ 24 ], among the 92 studies included in our analysis, only one used female animals, whereas 87 used male animals, and four did not report animal sex. This represents an important limitation of preclinical studies in regards to recent literature highlighting the effect of sex on OSA-associated cardiovascular dysfunctions [ 50 ].…”

Inhibition of Vascular Endothelial Cadherin Cleavage Prevents Elastic Fiber Alterations and Atherosclerosis Induced by Intermittent Hypoxia in the Mouse Aorta

“…To assess the IH-induced vascular remodeling and effect of the inhibitors, we first measured the intima-media thickness (IMT) in aortas of C57BL/6J mice exposed for 14 days to IH or N, treated by DMSO alone (control), acriflavine, pazopanib or saracatinib. We reproduced the known IH-induced elevation of IMT [12] and showed that all the inhibitors prevented this effect (Figure 3a,c). Second, we confirmed that IH alters the aortic elastic lamellae, and the elastic fibers (Figure 4a) in particular, by increasing the number of elastic lamella disruptions (Figure 4b,c) and reducing the thickness of the elastic lamellae (Figure 4d,e) without affecting the number of elastic lamellae (supplementary data S5).…”

“…The link between OSAS/IH and the structural and functional impairment of vascular endothelium has been well established in both patients and animal models. Indeed, IH induces various mechanisms, such as elevation of oxidative stress, activation of Hypoxia-Inducible Factor-1 (HIF-1) and its target genes, such as VEGF [5,6], low grade chronic inflammation and sympathetic activation that, in turn, lead to endothelial dysfunction, hypertension, vascular wall thickening and degradation of the elastic fibers [7][8][9][10][11] and atherosclerosis [3,12,13].…”

Crucial Role of Stromal Interaction Molecule-Activated TRPC-ORAI Channels in Vascular Remodeling and Pulmonary Hypertension Induced by Intermittent Hypoxia

“…Furthermore, OSA is associated with mild pulmonary hypertension with an incidence ranging from 20-50% ( Sajkov and McEvoy, 2009 ; Floras, 2018 ). Chronic intermittent hypoxia (CIH) is the main factor for develop systemic hypertension in OSA patients ( Somers et al, 2008 ; Dempsey et al, 2010 ) and animal exposed to CIH ( Del Rio et al, 2010 , 2014 ; Iturriaga et al, 2014 , 2021 ; Iturriaga, 2018 ; Harki et al, 2021 ). In addition, CIH produces vascular pulmonary remodeling and increases right ventricular systolic pressure (RVSP) in rodents ( Nisbet et al, 2009 ; Jin et al, 2014 , 2016 ; Iturriaga and Castillo-Galán, 2019 ; Castillo-Galán et al, 2020 ).…”