title: Early life stress in male mice induces superoxide production and endothelial dysfunction in adulthood.
abstract: 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.
authors.affiliation: Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Dao H
authors.initials: DH
authors.lastname: Ho
authors.affiliation: Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and Department of Medicine, Augusta University, Augusta, Georgia.
authors.forename: Mariah L
authors.initials: ML
authors.lastname: Burch
authors.affiliation: Department of Medicine, Augusta University, Augusta, Georgia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Musall
authors.affiliation: Department of Medicine, Augusta University, Augusta, Georgia.
authors.forename: Jacqueline B
authors.initials: JB
authors.lastname: Musall
authors.affiliation: Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Hyndman
authors.affiliation: Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and Department of Medicine, Augusta University, Augusta, Georgia pollockj@uab.edu.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Pollock
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001010:Anxiety, Separation / Q000523:psychology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D008297:Male; D008426:Maternal Deprivation; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008810:Mice, Inbred C57BL; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D013315:Stress, Psychological / Q000378:metabolism* / Q000503:physiopathology / Q000523:psychology; D013481:Superoxides / Q000378:metabolism*; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D014886:Weaning
chemical_list: D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D008562:Membrane Glycoproteins; D014665:Vasodilator Agents; D013481:Superoxides; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse
keywords: NADPH oxidase; early life stress; endothelial dysfunction; maternal separation with early weaning; superoxide