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

Ying Yang,Hui Liu,Li Xiong,Jing Wang,Junjian Zhang,Jieyang Ju,Min Deng

doi:10.3390/ijms18010003

Abstract

Hypoxia inducible factor 1α (HIF-1α), 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 HIF-1α to determine whether and how HIF-1α affects the disease processes and phenotypes of CCH. Lentivirus expressing HIF-1α small hairpin RNA was injected into the bilateral hippocampus and bilateral ventricles to knock down HIF-1α 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-1α 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-1α knockdown also disrupts upregulation of regulated downstream genes. Our findings suggest that HIF-1α-protects the brain from oxidative stress and inflammation response in the disease process of CCH. Accumulated HIF-1α during CCH mediates endogenous adaptive processes to defend against more severe hypoperfusion injury of the brain, which may provide a therapeutic benefit.

Highlights

Chronic crebral hypoperfusion (CCH) is a prevalent pathophysiological state in patients with Alzheimer’s disease (AD) and vascular dementia (VaD)
To ascertain the role of endogenous Hypoxia inducible factor 1α (HIF-1α) accumulation during CCH in rats, we used a loss of function approach by silencing HIF-1α expression using lentivirus-mediated shRNAi
Four weeks after 2-vessel occlusions (2VOs), there was a significant increase in the density of capillaries in the cortex of 2VO + pLVx-green fluorescent protein (GFP)-shCon rats compared with sham + pLVx-GFP-shCon rats (p < 0.05). Such an increase in capillaries was suppressed by pLVx-GFP-shHIF-1α, as the results showed that the density of capillaries in I2ntV

Summary

Introduction

Chronic crebral hypoperfusion (CCH) is a prevalent pathophysiological state in patients with Alzheimer’s disease (AD) and vascular dementia (VaD). Current studies have indicated that deranged energy metabolism, glial activation, apoptosis, oxidative stress, neuronal damage, and white matter lesions caused by cerebral hypoperfusion might be the pathophysiological mechanisms that contribute to cognitive impairment [2,3]. Gradual recovered cerebral blood flow (CBF), increased capillary diameter, neovascularization, and enhanced expression of vascular endothelial growth factor (VEGF) were noted in the cortex and hippocampus in rodent models of CCH [2], which indicates the compensatory or adaptive mechanisms. Because of the multifactorial pathogenesis of dementia, a large number of clinical trials which sought to identify protective strategies against this disease have failed, so the recruitment of endogenous neuroprotective pathways represents a potential strategy for developing therapeutics for the cognitive impairment. In the condition of CCH, hypoxia inducible factor 1 (HIF-1) is one of the most important transcription factors involved in endogenous adaptive response

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