title: Neurovascular coupling protects neurons against hypoxic injury via inhibition of potassium currents by generation of nitric oxide in direct neuron and endothelium cocultures.
abstract: This study examined the effect of neuron-endothelial coupling on the survival of neurons after ischemia and the possible mechanism underlying that effect. Whole-cell patch-clamp experiments were performed on cortical neurons cultured alone or directly cocultured with brain microvascular endothelial cells (BMEC). Propidium iodide (PI) and NeuN staining were performed to examine neuronal death following oxygen and glucose deprivation (OGD). We found that the neuronal transient outward potassium currents (IA) decreased in the coculture system, whereas the outward delayed-rectifier potassium currents (IK) did not. Sodium nitroprusside, a NO donor, enhanced BMEC-induced IAinhibition and nitro-l-arginine methylester, a NOS inhibitor, partially prevented this inhibition. Moreover, the neurons directly cocultured with BMEC showed more resistance to OGD-induced injury compared with the neurons cultured alone, and that neuroprotective effect was abolished by treatment with NS5806, an activator of the IA. These results indicate that vascular endothelial cells assist neurons to prevent hypoxic injury via inhibiting neuronal IAby production of NO in the direct neuron-BMEC coculture system. These results further provide direct evidence of functional coupling between neurons and vascular endothelial cells. This study clearly demonstrates that vascular endothelial cells play beneficial roles in the pathophysiological processes of neurons after hypoxic injury, suggesting that the improvement of neurovascular coupling or functional remodeling may become an important therapeutic target for preventing brain injury.
authors.affiliation: Institute of Biomedical Sciences and Department of Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, PR China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Research Center on Aging and Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, PR China.
authors.forename: Kun-Wei
authors.initials: KW
authors.lastname: Wu
authors.affiliation: Shanghai Key Laboratory of Clinical Geriatric Medicine, Research Center on Aging and Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, PR China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, PR China.
authors.forename: Zeng-Wei
authors.initials: ZW
authors.lastname: Kou
authors.affiliation: Shanghai Key Laboratory of Clinical Geriatric Medicine, Research Center on Aging and Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, PR China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, PR China.
authors.forename: Jia-Lin
authors.initials: JL
authors.lastname: Mo
authors.affiliation: Shanghai Key Laboratory of Clinical Geriatric Medicine, Research Center on Aging and Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, PR China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, PR China.
authors.forename: Xu-Xu
authors.initials: XX
authors.lastname: Deng
authors.affiliation: Institute of Biomedical Sciences and Department of Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, PR China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Research Center on Aging and Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, PR China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, PR China. Electronic address: fysun@shmu.edu.cn.
authors.forename: Feng-Yan
authors.initials: FY
authors.lastname: Sun
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018920:Coculture Techniques; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000172:deficiency*; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000066829:Neuroprotection / Q000187:drug effects / Q000502:physiology*; D000069336:Neurovascular Coupling / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D017207:Rats, Sprague-Dawley
chemical_list: D015221:Potassium Channels; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D005947:Glucose; D011188:Potassium
keywords: brain microvascular endothelial cells; neurovascular unit; nitric oxide; patch clamp; potassium channel; stroke