Abstract
Intracranial and extracranial arterial stenosis, the primary cause of chronic cerebral hypoperfusion (CCH), is a critical reason for the pathogenesis of vascular dementia and Alzheimer’s disease characterized by cognitive impairments. Our previous study demonstrated that limb remote ischemic conditioning (LRIC) improved cerebral perfusion in intracranial arterial stenosis patients. The current study aimed to test whether LRIC promotes angiogenesis and increases phosphorylated endothelial nitric oxide synthase (p-eNOS) activity in CCH rat model. Adult male Sprague-Dawley rats were randomly assigned to three different groups: sham group, bilateral carotid artery occlusion (2VO) group and 2VO+LRIC group. Cerebral Blood Flow (CBF) was measured with laser speckle contrast imager at 4 weeks. Cognitive testing was performed at four and six weeks after 2VO surgery. We demonstrated that LRIC treatment increased cerebral perfusion and improved the CCH induced spatial learning and memory impairment. Immunohistochemistry confirmed that LRIC prevented cell death in the CA1 region, and increased the number of vessels and angiogenesis in the hippocampus after 2VO. Western blot analysis shows that LRIC therapy significantly increased p-eNOS expression in the hippocampus when compared with 2VO rats. Moreover, eNOS inhibitor reduced the effect of LRIC on angiogenesis in the hippocampus and spatial learning and memory function. Our data suggested that LRIC promoted angiogenesis, which is mediated, in part, by eNOS/NO.
Highlights
Intracranial and extracranial arterial stenosis, the primary cause of chronic cerebral hypoperfusion (CCH), is a critical reason for the pathogenesis of vascular dementia and Alzheimer’s disease characterized by cognitive impairments
limb remote ischemic conditioning (LRIC) treatment significantly increased cerebral perfusion and improved the chronic cerebral hypoperfusion mediated spatial learning and memory impairment compared with the 2-vessel occlusion (2VO) rats
Additional analyses showed that LRIC treatment significantly increased phosphorylated endothelial nitric oxide synthase (p-Endothelial nitric oxide synthase (eNOS)) expression in the hippocampus, and NOS inhibitor, LNAME, suppressed the beneficial effect of LRIC on spatial learning and memory and angiogenesis in the hippocampus
Summary
Intracranial and extracranial arterial stenosis, the primary cause of chronic cerebral hypoperfusion (CCH), is a critical reason for the pathogenesis of vascular dementia and Alzheimer’s disease characterized by cognitive impairments. Our previous study demonstrated that limb remote ischemic conditioning (LRIC) improved cerebral perfusion in intracranial arterial stenosis patients. The current study aimed to test whether LRIC promotes angiogenesis and increases phosphorylated endothelial nitric oxide synthase (p-eNOS) activity in CCH rat model. We demonstrated that LRIC treatment increased cerebral perfusion and improved the CCH induced spatial learning and memory impairment. An ideal restorative approach for the prevention of tissue death after cerebral ischemia should promote vascular perfusion in the ischemic region. Our previous study showed that repetitive bilateral arm ischemic preconditioning reduced the incidence of stroke recurrence and improved cerebral perfusion in intracranial arterial stenosis patients. Any direct evidence that repetitive LRIC induces angiogenesis in CCH has not been postulated
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