Pro-angiogenic effects of resveratrol in brain endothelial cells: nitric oxide-mediated regulation of vascular endothelial growth factor and metalloproteinases.
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.
Departments of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Fabricio
F
Simão
Aline S
AS
Pagnussat
Ji Hae
JH
Seo
Deepti
D
Navaratna
Wendy
W
Leung
Josephine
J
Lok
Shuzhen
S
Guo
Christian
C
Waeber
Christianne G
CG
Salbego
Eng H
EH
Lo
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D045726:Metalloproteases / Q000096:biosynthesis*; D009569:Nitric Oxide / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D000099152:Cadherin 5
D043925:Angiogenesis Inducing Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD; D015820:Cadherins; D045726:Metalloproteases; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077185:Resveratrol; D013267:Stilbenes; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5; C467484:VEGFA protein, human