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Hypoxia Inducible Factor 1? Promotes Endogenous Adaptive Response in Rat Model of Chronic Cerebral Hypoperfusion.

ABSTRACT: Hypoxia inducible factor 1? (HIF-1?), a pivotal regulator of gene expression in response to hypoxia and ischemia, is now considered to regulate both pro-survival and pro-death responses depending on the duration and severity of the stress. We previously showed that chronic global cerebral hypoperfusion (CCH) triggered long-lasting accumulation of HIF-1? protein in the hippocampus of rats. However, the role of the stabilized HIF-1? in CCH is obscure. Here, we knock down endogenous HIF-1? to determine whether and how HIF-1? affects the disease processes and phenotypes of CCH. Lentivirus expressing HIF-1? small hairpin RNA was injected into the bilateral hippocampus and bilateral ventricles to knock down HIF-1? gene expression in the hippocampus and other brain areas. Permanent bilateral common carotid artery occlusions, known as 2-vessel occlusions (2VOs), were used to induce CCH in rats. Angiogenesis, oxidative stress, histopathological changes of the brain, and cognitive function were tested. Knockdown of HIF-1? prior to 2VO significantly exacerbates the impairment of learning and memory after four weeks of CCH. Mechanically, reduced cerebral angiogenesis, increased oxidative damage, and increased density of astrocytes and microglia in the cortex and some subregions of hippocampus are also shown after four weeks of CCH. Furthermore, HIF-1? knockdown also disrupts upregulation of regulated downstream genes. Our findings suggest that HIF-1?-protects the brain from oxidative stress and inflammation response in the disease process of CCH. Accumulated HIF-1? during CCH mediates endogenous adaptive processes to defend against more severe hypoperfusion injury of the brain, which may provide a therapeutic benefit.

SUBMITTER: Yang Y

PROVIDER: S-EPMC5297638 | biostudies-other | 2017 Jan

REPOSITORIES: biostudies-other

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Hypoxia Inducible Factor 1α Promotes Endogenous Adaptive Response in Rat Model of Chronic Cerebral Hypoperfusion.

Yang Ying Y Ju Jieyang J Deng Min M Wang Jing J Liu Hui H Xiong Li L Zhang Junjian J

International journal of molecular sciences 20170117 1

Hypoxia inducible factor 1α (<i>HIF-1α</i>), a pivotal regulator of gene expression in response to hypoxia and ischemia, is now considered to regulate both pro-survival and pro-death responses depending on the duration and severity of the stress. We previously showed that chronic global cerebral hypoperfusion (CCH) triggered long-lasting accumulation of HIF-1α protein in the hippocampus of rats. However, the role of the stabilized HIF-1α in CCH is obscure. Here, we knock down endogenous <i>HIF-1 ...[more]

PMID: 28106731

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Project description:ObjectiveCurrently, most models of vascular cognitive impairment are established by occluding the carotid arteries uni- or bilaterally to reduce the cerebral blood flow mimicking chronic cerebral hypoxia. Due to the sudden blood flow interruption, a gradual narrowing of the carotid artery cannot be completely imitated. This paper aims to establish a bilateral carotid stenosis model with mild cognitive dysfunction and mild white matter changes to simulate patients with vascular predementia.MethodsAged Wistar rats (18 months old) underwent either bilateral common carotid artery stenosis (BCAS) or occlusion (BCAO) surgery or a sham operation (control group). The cerebral blood flow in the frontal cortex was measured using Doppler flowmetry. Thirty days after surgery, cognitive function impairments were determined with the Morris water maze; cerebral magnetic resonance imaging was performed to detect changes in fractional anisotropy to assess white matter injuries, and histological studies were performed.ResultsThe aged rats in the BCAS group showed a more gradual cerebral blood flow reduction and a lower mortality rate (11%) compared to rats in the BCAO group. The water maze test revealed a more marginal impairment affecting spatial learning and memory in rats with BCAS than in rats with BCAO. Diffusion tensor imaging detected white matter injuries in the hippocampus and cerebral cortex of BCAS rats. Particularly, a small portion of nerve fibers of the lateral somatosensory cortex was significantly different between rats of the BCAO and BCAS groups. In the BCAS group, the microscopic structure of the hippocampal CA1 region changed slightly after 30 days and sustained a slight mitochondrial crista crack. Fluorescence staining indicated that the number of GFAP-positive cells was increased in rat brains of the BCAS group, and this phenomenon was even more pronounced in the BCAO group. The hnRNPA2/B1 and GABAAR-α1 expression levels were significantly decreased in the hippocampus of rats with BCAS compared to those of controls.ConclusionSevere bilateral carotid stenosis induced mild cognitive dysfunction and slight structural changes in the brains of aged rats. Thus, a chronic cerebral hypoperfusion model was successfully established.

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Hypoxia Inducible Factor 1? Promotes Endogenous Adaptive Response in Rat Model of Chronic Cerebral Hypoperfusion.

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Hypoxia Inducible Factor 1α Promotes Endogenous Adaptive Response in Rat Model of Chronic Cerebral Hypoperfusion.

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