Early life stress in male mice induces superoxide production and endothelial dysfunction in adulthood
Open accessAbstract
Early life stress (ELS) is a risk for cardiovascular disease in adulthood although very little mechanistic insight is available. Because oxidative stress and endothelial dysfunction are major contributors to cardiovascular risk, we hypothesized that ELS induces endothelial dysfunction in adult male mice via increased superoxide production. Studies employed a mouse model of ELS, maternal separation with early weaning (MSEW), in which litters were separated from the dam for 4 h/day [ postnatal days (PD) 2–5] and 8 h/day (PD6-16), and weaned at PD17. Control litters remained undisturbed until weaning at PD21. When compared with control mice, thoracic aortic rings from adult male MSEW mice displayed significant endothelial dysfunction that was reversed by the superoxide scavenger, polyethylene glycol-superoxide dismutase (PEG-SOD). PEG-SOD-inhibitable superoxide production by aortae from MSEW mice was significantly greater than observed in control aortae, although unaffected by nitric oxide synthase inhibition, suggesting that uncoupled nitric oxide synthase was not responsible for the accelerated superoxide production. Aortic SOD expression, plasma SOD activity, and total antioxidant activity were similar in MSEW and control mice, indicating unaltered antioxidant capacity in MSEW mice. Increased expression of the NADPH oxidase subunits, NOX2 and NOX4, was evident in the aortae of MSEW mice. Moreover, endothelial dysfunction and superoxide production in MSEW mice was reversed with the NADPH oxidase inhibitor, apocynin, indicating increased NADPH oxidase-dependent superoxide production and endothelial dysfunction. The finding that MSEW induces superoxide production and endothelial dysfunction in adult mice may provide a mechanistic link between ELS and adult cardiovascular disease risk.
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Animal findings suggest that ELS/CT-related significant endothelial dysfunction is linked to increased superoxide production.
“Animal findings suggest that ELS/CT-related significant endothelial dysfunction is linked to increased superoxide production (275)”
From Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation (2019) · cites this paper as [275]
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- Authors
- Ho, D. H., Burch, M. L., Musall, B., Musall, J. B., Hyndman, K. A., & Pollock, J. S.
- Affiliations
- University of Alabama at Birmingham (US)
- Augusta University (US)
- Corresponding author
- Pollock, Jennifer S.
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2016-05-01
- Volume
- 310
- Issue
- 9
- Pages
- H1267-H1274
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- PMC
- PMC4867391
- OpenAlex
- W2275060080
- Semantic Scholar
- 0923d08b62dc4ae20281114d01b3688a9185dfd3
- Cited by
- 34
- References
- 41
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 8 · 2020: 3 · 2019: 3 · 2018: 3 · 2016: 1
- FWCI
- 1.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI) (HL69999, HL116145)
- American Heart Association (AHA) (11POST7240008)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- early life stress, maternal separation, endothelial dysfunction, superoxide production, oxidative stress, NADPH oxidase, NOX2, NOX4, apocynin, aorta, cardiovascular risk, uncoupled nitric oxide synthase, antioxidant capacity
- MeSH terms
- NADPH Oxidase 2, NADPH Oxidase 4, Age Factors, Animals, Animals, Newborn, Anxiety, Separation, Aorta, Thoracic, Disease Models, Animal, Dose-Response Relationship, Drug, Endothelium, Vascular, Enzyme Inhibitors, Female, Male, Maternal Deprivation, Membrane Glycoproteins, Mice, Inbred C57BL, Stress, Psychological, Superoxides, Vasodilation, Vasodilator Agents, Weaning, Up-Regulation, Free Radical Scavengers, Oxidative Stress, NADPH Oxidases
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