Cyclic nucleotide phosphodiesterases (PDEs) and endothelial function in ischaemic stroke. A review |
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| Institution: | 1. Stroke Unit and Neurovascular Research Unit, Department of Neurology, Herlev Gentofte Hospital, Herlev Ringvej 75, Herlev, Denmark;2. Faculty of Health and Medical Sciences, University of Copenhagen, Denmark;3. Clinical Neuroscience, Molecular & Clinical Sciences Research Institute, St George''s University of London, Cranmer Terrace, London SW17 0RE, UK;1. Department of Biology, York University, Toronto, ON M3J 1P3, Canada;2. Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, China;3. The Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA;4. Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, ON M3J1P3, Canada;5. Division of Cardiology, University Health Network, Toronto, ON M5S 3E2, Canada;1. Department of Medicine, University of Miami/Jackson Memorial Hospital, Miami, Florida;2. Division of Cardiology, Duke University Medical Center, Durham, North Carolina;3. Department of Medicine, University of Minnesota, Minneapolis, Minnesota;4. Division of Cardiology, University of Mississippi Medical Center, Jackson, Mississippi;5. Advanced Heart Failure Program, Baptist Health South Florida, Miami, Florida;6. Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina;1. Department of Neurology, Copenhagen University Hospital Glostrup, DK-2600 Glostrup, Denmark;2. Acute Stroke Unit, Copenhagen University Hospital Glostrup, DK-2600 Glostrup, Denmark;3. Lundbeck Foundation Center for Neurovascular Signaling, Glostrup Research Institute, Glostrup Hospital, Denmark;4. Dept. Neurology, Neurovascular Research Unit, Copenhagen, University Hospital Herlev, Denmark |
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| Abstract: | BackgroundEndothelial dysfunction is a hallmark of cerebrovascular disease, including ischemic stroke. Modulating endothelial signalling by cyclic nucleotides, cAMP and cGMP, is a potential therapeutic target in stroke. Inhibitors of the cyclic nucleotide degrading phosphodiesterase (PDE) enzymes may restore cerebral endothelial function. Current knowledge on PDE distribution and function in cerebral endothelial cells is sparse. This review explores data on PDE distribution and effects of PDEi in cerebral endothelial cells and identifies which PDEs are potential treatment targets in stroke.MethodWe performed a systematic search of electronic databases (Medline and Embase). Our search terms were cerebral ischaemia, cerebral endothelial cells, cyclic nucleotide, phosphodiesterase and phosphodiesterase inhibitors.ResultsWe found 23 publications which described effects of selective inhibitors of only three PDE families on endothelial function in ischemic stroke. PDE3 inhibitors (PDE3i) (11 publications) and PDE4 inhibitors (PDE4i) (3 publications) showed anti-inflammatory, anti-apoptotic or pro-angiogenic effects. PDE3i also reduced leucocyte infiltration and MMP-9 expression. Both PDE3i and PDE4i increased expression of tight junction proteins and protected the blood-brain barrier. PDE5 inhibitors (PDE5i) (6 publications) reduced inflammation and apoptosis. In preclinical models, PDE5i enhanced cGMP/NO signalling associated with microvascular angiogenesis, increased cerebral blood flow and improved functional recovery. Non-specific PDEi (3 publications) had mainly anti-inflammatory effects.ConclusionThis review demonstrates that non-selective and selective PDEi of PDE3, PDE4 and PDE5 modulated endothelial function in cerebral ischemic stroke by regulating processes involved in vascular repair and neuroprotection and thus reduced cell death and inflammation. Of note, they promoted angiogenesis, microcirculation and improved functional recovery; all are important in stroke prevention and recovery, and effects should be further evaluated in humans. |
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