CREB activation mediates VEGF-A's protection of neurons and cerebral vascular endothelial cells.
Hypoxic ischemia (HI) in neonates causes significant neurodevelopmental sequelae. Pharmacological agents designed to target specific transcription factors expressed in neurons and vasculature may provide powerful therapy against HI. Vascular endothelial growth factor-A (VEGF-A) and cAMP response element-binding protein (CREB) both underlie learning and memory, and survival of the nervous system. We examined whether CREB activation is a shared pathway underlying VEGF-A's protection in neurons and cerebral vascular endothelial cells. VEGF-A was used in a HI model of rat pups and in oxygen-glucose-deprivation (OGD) models of immortalized H19-7 neurons and b.End3 cerebral vascular endothelial cells. We found that VEGF-A activated VEGF receptor-2 (VEGFR-2), phosphorylated CREB in neurons and endothelial cells, and protected against HI, and inhibiting VEGFR-2 before VEGF-A reduced the protective effect of VEGF-A in rat pups. VEGF-A also up-regulated VEGFR-2 and phosphorylated CREB, and protected H19-7 neurons and b.End3 endothelial cells against OGD. Inhibiting VEGFR-2 and extracellular signal-regulated kinase (ERK), respectively, reduced VEGF-A-induced CREB phosphorylation and protection of H19-7 and b.End3 cells against OGD. Transfecting H19-7 and b.End3 cells with a serine-133 phosphorylation mutant CREB also inhibited VEGF-A's protection of both types of cells. We conclude that CREB phosphorylation through VEGFR-2/ERK signaling is the shared pathway that underlies VEGF-A's protection of neurons and vascular endothelial cells.
Lee
Hsueh-Te
HT
Department of Pediatrics, National Cheng Kung University College of Medicine, Tainan, Taiwan.
Chang
Ying-Chao
YC
Tu
Yi-Fang
YF
Huang
Chao-Ching
CC
D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology / Q000517:prevention & control*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000072483:Placenta Growth Factor; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011257:Pregnancy Proteins / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection / Q000379:methods; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
D002867:Chromones; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D007211:Indoles; D009025:Morpholines; C000608038:Pgf protein, rat; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011257:Pregnancy Proteins; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D000072483:Placenta Growth Factor; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D012694:Serine; C116890:Semaxinib; D050882:CREB-Binding Protein; D040301:Vascular Endothelial Growth Factor Receptor-2; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose