The phosphatidylinositol‐3 kinase/Akt pathway mediates VEGF's neuroprotective activity and induces blood brain barrier permeability after focal cerebral ischemia

Abstract

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.

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

“…The increased expression of antiinflammatory cytokines (IL4, IL10, and IL13) following pFUS+MB could limit the extent of injury, promote neuronal survival, and induce microglial apoptosis (69)(70)(71)(72). Moreover, the increases in EPO (69), SDF1α (7,73), VEGF (74), BDNF (65,75), and G-CSF (66) could provide neuroprotection and stimulate neurogenesis and stem cell tropism to sonicated tissue. It is possible that the significantly delayed expression of BDNF protein along with induced antiapoptotic Bcl2a1 and Birc3 mRNA would have limited the extent of apoptosis and reactive microglia by 24 h postsonication (65,75).…”

Neuroprotection by Dimethyloxalylglycine following Permanent and Transient Focal Cerebral Ischemia in Rats

“…Mice lacking eNOS expression show a greater degree of hemodynamic compromise after MCAO and hence the product of eNOS activity (i.e., NO) may protect the brain after focal cerebral ischemia by improving blood flow within the penumbral zone (Lo et al, 1996). VEGF can have a dual function in the brain mediating both neuroprotection and BBB permeability through VEGF/VEGFR2/Flk1 and PI3K/Akt pathways (Kilic et al, 2006;Laudenbach et al, 2007;Wang et al, 2007). Recently, DMOG treatment of rat pups after cerebral ischemia led to increased BBB permeability and brain edema in association with raised levels of VEGF (Chen et al, 2008).…”

Protective effect of ad-vegf-bone mesenchymal stem cells on cerebral infarction

“…The tissue-type plasminogen activator substance, which is used to treat cerebral infarction, is the only drug approved by the U.S. Food and Drug Administration. However, given the secondary bleeding risk induced by thrombolytic therapy, only 3% of the patients with cerebral infarction can be treated with thrombolytic agents (11,24). Based on its multi-directional differentiation and proliferation ability, transplanting bone mesenchymal stem cells (BMSCs) for CVD treatment has attracted increasing attention.…”