Deficiency of superoxide dismutase promotes cerebral vascular hypertrophy and vascular dysfunction in hyperhomocysteinemia

被引:26
作者
Dayal, Sanjana [1 ]
Baumbach, Gary L. [2 ]
Arning, Erland [3 ]
Bottiglieri, Teodoro [3 ]
Faraci, Frank M. [1 ,4 ]
Lentz, Steven R. [1 ]
机构
[1] Univ Iowa, Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA
[2] Univ Iowa, Carver Coll Med, Dept Pathol, Iowa City, IA USA
[3] Baylor Inst Metab Dis, Dallas, TX USA
[4] Univ Iowa, Carver Coll Med, Dept Pharmacol, Iowa City, IA USA
来源
PLOS ONE | 2017年 / 12卷 / 04期
关键词
SMOOTH-MUSCLE-CELLS; NITRIC-OXIDE; B-VITAMINS; FOLIC-ACID; MICE DEFICIENT; HOMOCYSTEINE; STROKE; ARTERIOLES; PREVENTION; SYNTHASE;
D O I
10.1371/journal.pone.0175732
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
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页数:15
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