Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models. Hypoxia has been shown to be a major inducer of VEGF gene transcription. The tyrosine kinases Flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2) are high-affinity VEGF receptors. The role of VEGF in developmental angiogenesis is emphasized by the finding that loss of a single VEGF allele results in defective vascularization and early embryonic lethality. VEGF is critical also for reproductive and bone angiogenesis. Substantial evidence also implicates VEGF as a mediator of pathological angiogenesis. In situ hybridization studies demonstrate expression of VEGF mRNA in the majority of human tumors. Anti-VEGF monoclonal antibodies and other VEGF inhibitors block the growth of several tumor cell lines in nude mice. Clinical trials with various VEGF inhibitors in a variety of malignancies are ongoing. Very recently, an anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the Food and Drug Administration as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. Furthermore, VEGF is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration.

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Vascular endothelial growth factor: basic science and clinical progress.

A neurotrophic model for stress-related mood disorders.

Mechanisms and functional implications of adult neurogenesis.

Byproducts of normal mitochondrial metabolism and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca2+, etc., which must be normalized. Evidence suggests that brief mitochondrial permeability transition pore (mPTP) openings play an important physiological role maintaining healthy mitochondria homeostasis. Adaptive and maladaptive responses to redox stress may involve mitochondrial channels such as mPTP and inner membrane anion channel (IMAC). Their activation causes intra- and intermitochondrial redox-environment changes leading to ROS release. This regenerative cycle of mitochondrial ROS formation and release was named ROS-induced ROS release (RIRR). Brief, reversible mPTP opening-associated ROS release apparently constitutes an adaptive housekeeping function by the timely release from mitochondria of accumulated potentially toxic levels of ROS (and Ca2+). At higher ROS levels, longer mPTP openings may release a ROS burst leading to destruction of mitochondria, and if propagated from mitochondrion to mitochondrion, of the cell itself. The destructive function of RIRR may serve a physiological role by removal of unwanted cells or damaged mitochondria, or cause the pathological elimination of vital and essential mitochondria and cells. The adaptive release of sufficient ROS into the vicinity of mitochondria may also activate local pools of redox-sensitive enzymes involved in protective signaling pathways that limit ischemic damage to mitochondria and cells in that area. Maladaptive mPTP- or IMAC-related RIRR may also be playing a role in aging. Because the mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, we discuss all of the known ROS-producing sites (shown in vitro) and their relevance to the mitochondrial ROS production in vivo.

Mitochondrial Reactive Oxygen Species (ROS) and ROS-Induced ROS Release

Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis

Induction of vascular endothelial growth factor and hypoxia-inducible factor-1α by global ischemia in rat brain

Vascular endothelial growth factor (VEGF),which is prominently involved in angiogenesis, also exerts direct effects on neurons, leading to neurite extension, neuroprotection, and neurogenesis. However, the signal transduction pathways employed by VEGF in neurons are incompletely understood. We investigated the molecular mechanisms through which VEGF stimulates neurogenesis in primary cultures of rat cerebral cortical neurons. VEGF increased neurite outgrowth, measured using a colorimetric assay for cresyl violet staining of neuronal processes, with half-maximal enhancement at 10 ng/mL and maximal, approximately 60% enhancement at 30-100 ng/mL. The effect of VEGF was not reproduced by VEGF-B or placental growth factor, but was blocked by SU1498, consistent with a VEGFR2 receptor-mediated process. VEGF-induced neurite outgrowth was also blocked by the ROK inhibitor Y27632 and the Rho inhibitors sulindac and Clostridium botulium exoenzyme C3, and was accompanied by Y27632-sensitive phosphorylation of cofilin, a downstream mediator of Rho/ROK signaling. We conclude that VEGF promotes neurite outgrowth from cerebral cortical neurons by interacting with VEGFR2 and activating Rho/ROK signaling pathways.

Vascular endothelial growth factor stimulates neurite outgrowth from cerebral cortical neurons via Rho kinase signaling.

Neuroglobin (Ngb), a vertebrate globin expressed primarily in neurons, is induced by and protects against neuronal hypoxia and cerebral ischemia. To investigate the spectrum and mechanism of Ngb's neuroprotective action, we studied the effect of transgenic overexpression of Ngb on NMDA and beta-amyloid (Abeta) toxicity in murine cortical neuron cultures in vitro and on the phenotype of Alzheimer's disease (AD) transgenic (APP(Sw,Ind)) mice. Compared with cortical neuron cultures from wild-type mice, cultures from Ngb-overexpressing transgenic (Ngb-Tg mice) were resistant to the toxic effects of NMDA and Abeta(25-35), as measured by polarization of cell membrane lipid rafts, mitochondrial aggregation, lactate dehydrogenase release, and nuclear fragmentation. In addition, compared with APP(Sw,Ind) mice, double-transgenic (Ngb-Tg x APP(Sw,Ind)) mice showed reductions in thioflavin-S-stained extracellular Abeta deposits, decreased levels of Abeta(1-40) and Abeta(1-42), and improved behavioral performance in a Y-maze test of spontaneous alternations. These findings suggest that the spectrum of Ngb's neuroprotective action extends beyond hypoxic-ischemic insults. Ngb may protect neurons from NMDA and Abeta toxicity by inhibiting the formation of a death-signaling membrane complex, and interventions that increase Ngb expression could have therapeutic application in AD and other neurodegenerative disorders.

Neuroglobin attenuates β-amyloid neurotoxicity in vitro and transgenic Alzheimer phenotype in vivo

Vascular endothelial growth factor (VEGF) is an angiogenic factor with neurotrophic effects in the peripheral nervous system. To determine if VEGF can also promote the survival of central neurons, we examined its effect on HN33 (mouse hippocampal neuron × neuroblastoma) cells deprived of serum. Serum-deprived HN33 cells expressed VEGFR-2 receptors, which, in the presence of VEGF, interacted with the downstream signaling molecules phosphatidylinositol 3′-kinase and phospho-Akt, as demonstrated by immunoprecipitation and Western blotting. Treatment of serum-deprived HN33 cells with VEGF also stimulated the phosphorylation of IκB-α and nuclear translocation of the transcription factor NF-κB. Withdrawal of serum for 24 h reduced HN33 cell viability by ∼50% in the absence of VEGF, but by only ∼20% in the presence of 100 ng/mL of VEGF. These findings support a neurotrophic role for VEGF in the central nervous system, which may be mediated through VEGFR-2 receptors, the protein kinases phosphatidylinositol 3′-kinase and Akt, and the transcription factor NK-κB. Thus, VEGF, like other neurotrophic factors, could exert protective effects in acute or chronic neurodegenerative disorders.

Xiao Ou Mao

Papers

Induction of vascular endothelial growth factor and hypoxia-inducible factor-1α by global ischemia in rat brain

Vascular endothelial growth factor stimulates neurite outgrowth from cerebral cortical neurons via Rho kinase signaling.

Neuroglobin attenuates β-amyloid neurotoxicity in vitro and transgenic Alzheimer phenotype in vivo

Vascular endothelial growth factor rescues HN33 neural cells from death induced by serum withdrawal

Alzheimer's disease drugs promote neurogenesis.