Pro-Angiogenic Effects of Resveratrol in Brain Endothelial Cells: Nitric Oxide-Mediated Regulation of Vascular Endothelial Growth Factor and Metalloproteinases

• Published in: Journal of cerebral blood flow and metabolism 2012-05, Vol.32 (5), p.884-895
• Main Authors: Simão, Fabricio, Pagnussat, Aline S, Seo, Ji Hae, Navaratna, Deepti, Leung, Wendy, Lok, Josephine, Guo, Shuzhen, Waeber, Christian, Salbego, Christianne G, Lo, Eng H
• Format: Article
• Language: English
• Subjects: AKT protein; Angiogenesis; Angiogenesis Inducing Agents - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Antigens, CD - metabolism; Biological and medical sciences; Brain - metabolism; Brain - pathology; Brain injury; Cadherins - metabolism; catenin; Cell migration; Cell proliferation; Cerebral blood flow; Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges; Cytoskeleton; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - pathology; Extracellular signal-regulated kinase; Fundamental and applied biological sciences. Psychology; Humans; MAP kinase; MAP Kinase Signaling System - drug effects; Matrix metalloproteinase; Medical sciences; Metalloproteases - biosynthesis; Neurology; Nitric oxide; Nitric Oxide - metabolism; Nitric-oxide synthase; Original; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Resveratrol; Signal transduction; Stilbenes - pharmacology; Stress; Stroke; Stroke - drug therapy; Stroke - metabolism; Stroke - pathology; Vascular diseases and vascular malformations of the nervous system; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - biosynthesis; Vertebrates: nervous system and sense organs
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2012.2

Resveratrol may be a powerful way of protecting the brain against a wide variety of stress and injury. Recently, it has been proposed that resveratrol not only reduces brain injury but also promotes recovery after stroke. But the underlying mechanisms are unclear. Here, we tested the hypothesis that resveratrol promotes angiogenesis in cerebral endothelial cells and dissected the signaling pathways involved. Treatment of cerebral endothelial cells with resveratrol promoted proliferation, migration, and tube formation in Matrigel assays. Consistent with these pro-angiogenic responses, resveratrol altered endothelial morphology resulting in cytoskeletal rearrangements of β-catenin and VE-cadherin. These effects of resveratrol were accompanied by activation of phosphoinositide 3 kinase (PI3-K)/Akt and Mitogen-Activated Protein Kinase (MAPK)/ERK signaling pathways that led to endothelial nitric oxide synthase upregulation and increased nitric oxide (NO) levels. Subsequently, elevated NO signaling increased vascular endothelial growth factor and matrix metalloproteinase levels. Sequential blockade of these signaling steps prevented resveratrol-induced angiogenesis in cerebral endothelial cells. These findings provide a mechanistic basis for the potential use of resveratrol as a candidate therapy to promote angiogenesis and neurovascular recovery after stroke.