Journal article
Deficiency of superoxide dismutase promotes cerebral vascular hypertrophy and vascular dysfunction in hyperhomocysteinemia
PloS one, Vol.12(4), pp.e0175732-e0175732
2017
DOI: 10.1371/journal.pone.0175732
PMCID: PMC5393600
PMID: 28414812
Abstract
There is an emerging consensus that hyperhomocysteinemia is an independent risk factor for cerebral vascular disease and that homocysteine-lowering therapy protects from ischemic stroke. However, the mechanisms by which hyperhomocysteinemia produces abnormalities of cerebral vascular structure and function remain largely undefined. Our objective in this study was to define the mechanistic role of superoxide in hyperhomocysteinemia-induced cerebral vascular dysfunction and hypertrophy. Unlike previous studies, our experimental design included a genetic approach to alter superoxide levels by using superoxide dismutase 1 (SOD1)-deficient mice fed a high methionine/low folate diet to produce hyperhomocysteinemia. In wild-type mice, the hyperhomocysteinemic diet caused elevated superoxide levels and impaired responses to endothelium-dependent vasodilators in cerebral arterioles, and SOD1 deficiency compounded the severity of these effects. The cross-sectional area of the pial arteriolar wall was markedly increased in mice with SOD1 deficiency, and the hyperhomocysteinemic diet sensitized SOD1-deficient mice to this hypertrophic effect. Analysis of individual components of the vascular wall demonstrated a significant increase in the content of smooth muscle and elastin. We conclude that superoxide is a key driver of both cerebral vascular hypertrophy and vasomotor dysfunction in this model of dietary hyperhomocysteinemia. These findings provide insight into the mechanisms by which hyperhomocysteinemia promotes cerebral vascular disease and ischemic stroke.
Details
- Title: Subtitle
- Deficiency of superoxide dismutase promotes cerebral vascular hypertrophy and vascular dysfunction in hyperhomocysteinemia
- Creators
- Sanjana Dayal - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of AmericaGary L Baumbach - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of AmericaErland Arning - Baylor Institute of Metabolic Disease, Dallas, Texas, United States of AmericaTeodoro Bottiglieri - Baylor Institute of Metabolic Disease, Dallas, Texas, United States of AmericaFrank M Faraci - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of AmericaSteven R Lentz - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.12(4), pp.e0175732-e0175732
- DOI
- 10.1371/journal.pone.0175732
- PMID
- 28414812
- PMCID
- PMC5393600
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Publisher
- Public Library of Science; United States
- Grant note
- DOI: 10.13039/100000968, name: American Heart Association; DOI: 10.13039/100000050, name: National Heart, Lung, and Blood Institute, award: HL063943; DOI: 10.13039/100000065, name: National Institute of Neurological Disorders and Stroke, award: NS024621; DOI: 10.13039/100000050, name: National Heart, Lung, and Blood Institute, award: HL062984; DOI: 10.13039/100000002, name: National Institutes of Health, award: HL113863; DOI: 10.13039/501100001674, name: Fondation Leducq; DOI: 10.13039/100000738, name: U.S. Department of Veterans Affairs, award: BX001399
- Language
- English
- Date published
- 2017
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984070389102771
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