Intermittent Hypoxia Induces Early Functional Cardiovascular Remodeling in Mice
Abstract
Rationale: Intermittent hypoxia, a hallmark of sleep apnea, is a major factor for hypertension and impaired vasoreactivity. Objectives: To examine the temporal occurrence of these two outcomes in order to provide insight into mechanisms and early cardiovascular disease identification. Methods: Functional and structural cardiovascular alterations were assessed in C57BL6 mice exposed to intermittent hypoxia (21–4% FiO2, 30-s cycle, 8 h/d) or air for up to 35 days. Blood pressure, heart rate, and urinary catecholamines were measured at Days 1 and 14. Hindquarter vasoreactivity was assessed at Days 14 and 35, including vasoconstriction to norepinephrine, endothelium-, and non–endothelium-dependent vasodilation. Aorta, heart, and hindquarter skeletal muscles were immunostained for vascular markers PECAM-1 and collagen IV. Measurements and Main Results: Hemodynamic alterations occurred from Day 1, characterized by blood pressure surges with bradytachyarrhythmia driven by cyclic hypoxia. At Day 14, blood pressure at normoxia was elevated, with predominant diastolic increase. With hypoxia, vasopressive catecholamines were elevated, blood pressure surged with a lower hypoxic threshold, whereas heart rate fluctuations decreased. Histologic alterations started from Day 14, with decreased endothelial PECAM-1 expression in descending aorta and left heart. Impaired peripheral vasoreactivity occurred at Day 35, including hypervasoconstriction to norepinephrine secondary to sympathetic hyperactivity, without changes in pre- and postsynaptic α-adrenoceptors or in endothelium- and non–endothelium-dependent vasodilation. Conclusions: Intermittent hypoxia induces sequential cardiovascular events suggesting increased chemoreflex and depressed baroreflex, resulting in sympathoadrenal hyperactivity, early hemodynamic alterations with proximal histologic remodeling, and delayed changes in peripheral vasoreactivity. Such early alterations before overt cardiovascular disease strengthen the need for identifying at-risk individuals for systematic treatment.
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Increased sympathetic activity is seen in both animal models subjected exclusively to intermittent hypoxia and healthy human volunteers exposed to intermittent hypoxia in a "tent."
“Indeed, increased sympathetic activity is seen in both animal models subjected exclusively to intermittent hypoxia258 and healthy human volunteers exposed to intermittent hypoxia in a “tent.”259”
From Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association (2018) · cites this paper as [258]
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- Authors
- Dematteis, M., Julien, C., Guillermet, C., Sturm, N., Lantuejoul, S., Mallaret, M., Lévy, P., & Gozal, E.
- Affiliations
- INSERM ERI17, Grenoble, France
- University of Louisville (US)
- Hôpital Albert Michallon (FR)
- Département de Pathologie, CHU, Hôpital A. Michallon, Grenoble, France
- Venue
- American Journal of Respiratory and Critical Care Medicine
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-01
- Volume
- 177
- Issue
- 2
- Pages
- 227-235
- ISSN
- 1073-449X (ISSN-L)
- 1535-4970
- OpenAlex
- W1977085288
- Cited by
- 167
- References
- 31
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 1 · 2023: 7 · 2022: 9 · 2021: 8 · 2020: 6 · 2019: 11 · 2018: 9 · 2017: 5 · 2016: 4 · 2015: 9 · 2014: 13 · 2013: 11 · 2012: 15
- FWCI
- 8.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Respiratory and Critical Care Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Obstructive Sleep Apnea Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Keywords
- intermittent hypoxia, sleep apnea, cardiovascular remodeling, hypertension, vasoreactivity, catecholamines, baroreflex, chemoreflex, endothelial dysfunction, CD31, norepinephrine-induced vasoconstriction, alpha-adrenergic receptors, mice
- MeSH terms
- Acetylcholine, Animals, Hypoxia, Blood Pressure, Catecholamines, Disease Models, Animal, Heart Rate, Immunohistochemistry, Male, Mice, Inbred C57BL, Myocardium, Sleep Apnea Syndromes, Vasoconstriction, Vasodilation, Ventricular Remodeling, Mice, Transforming Growth Factor beta1
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