Limb Ischemic Conditioning Improved Cognitive Deficits via eNOS-Dependent Augmentation of Angiogenesis after Chronic Cerebral Hypoperfusion in Rats

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.

Remote ischemic conditioning counteracts the intestinal damage of necrotizing enterocolitis by improving intestinal microcirculation

“…Previous experimental studies in the heart and the brain have demonstrated that RIC targets microcirculation in the distant ischemic target organ 33 – 36 . RIC enhanced collateral circulation in a murine model of focal cerebral ischemia 33 , elevated cerebral blood flow in the rat ischemic brain during stroke recovery 34 , and improved coronary collateral circulation in a rabbit model of myocardial ischemia 35 . These reports suggest a potential protection to organs via improved circulation.…”

Animal Models of Chronic Cerebral Hypoperfusion: From Mouse to Primate

“…Cortical gray matter disorders vary with age, lineage, and surgical technique, and there is a discrepancy among reports [34]. Although no morphological abnormalities have been found in the cerebral cortex and hippocampus, one study reported mild cell shedding mainly in the hippocampal CA1 region [44].…”

<p>Effects of Remote Ischemic Conditioning on Cerebral Hemodynamics in Ischemic Stroke</p>

“…Intraperitoneal injection of NOS inhibitors can reverse this phenomenon. 72 Moreover, RIC treatment could up-regulate the content of nitrite in the plasma of mice, and the up-regulation of nitrite was related to the increase of CBF. 73 Hoda et al reported that RIC up-regulated the expression of eNOS mRNA in blood vessels of the regulatory site by about 10 times, and increased the plasma concentration of NO.…”