The phosphatidylinositol-3 kinase/Akt pathway mediates VEGF's neuroprotective activity and induces blood brain barrier permeability after focal cerebral ischemia.
Based on its trophic influence on neurons and vascular cells, vascular endothelial growth factor (VEGF) is a promising candidate for stroke treatment. VEGF's survival-promoting effects are purchased at the expense of an increased blood brain barrier permeability, which potentially compromises tissue survival. The mechanisms via which VEGF protects the brain against ischemia remained unknown. We examined signaling pathways underlying VEGF's neuroprotective activity in our transgenic mouse line, which expresses human VEGF165 under a neuron-specific enolase (NSE) promoter. We show that VEGF receptor-2 (Flk-1) is expressed on ischemic neurons and astrocytes and is activated by VEGF. Following 90-min episodes of middle cerebral artery occlusion, VEGF increased phosphorylated (but not total) Akt and ERK-1/-2 and reduced phosphorylated mitogen activated protein kinase/p38 and c-Jun NH2-terminal kinase (JNK)-1/-2 levels, at the same time decreasing inducible NO synthase expression in ischemic neurons. Inhibition of Akt with Wortmannin reversed VEGF's neuroprotective properties, diminished brain swelling, and restored the vascular permeability induced by VEGF to below levels in WT animals. The aggravation of brain injury by Wortmannin was associated with the restitution of p38, but not of JNK-1/-2, ERK-1/-2, or inducible NOS (iNOS). Our data demonstrate that VEGF mediates both neuroprotection and blood brain barrier permeability via the phosphatidylinositol-3 kinase (PI3K)/Akt pathway. Based on our observation that VEGF neuroprotection and vascular leakage depend on PI3K/Akt, which is putatively regulated by VEGF receptor-2, we predict that it may not easily be possible to make use of VEGF's neuroprotective function without accepting its unfavorable consequence, the increased vascular permeability.
Kilic
Ertugrul
E
Department of Neurology, University Hospital Zurich, Frauenklinikstr. 26, CH-8091 Zurich, Switzerland. ertugrul.kilic@usz.ch
Kilic
Ulkan
U
Wang
Yaoming
Y
Bassetti
Claudio L
CL
Marti
Hugo H
HH
Hermann
Dirk M
DM
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002545:Brain Ischemia / Q000097:blood / Q000201:enzymology* / Q000378:metabolism; D002199:Capillary Permeability; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D020928:Mitogen-Activated Protein Kinases; D018696:Neuroprotective Agents; D052247:Nitric Oxide Synthase Type II; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077191:Wortmannin; C467484:VEGFA protein, human