VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia

Abstract

Vascular endothelial growth factor (VEGF) is an angiogenic protein with therapeutic potential in ischemic disorders, including stroke. VEGF confers neuroprotection and promotes neurogenesis and cerebral angiogenesis, but the manner in which these effects may interact in the ischemic brain is poorly understood. We produced focal cerebral ischemia by middle cerebral artery occlusion for 90 minutes in the adult rat brain and measured infarct size, neurological function, BrdU labeling of neuroproliferative zones, and vWF-immunoreactive vascular profiles, without and with intracerebroventricular administration of VEGF on days 1-3 of reperfusion. VEGF reduced infarct size, improved neurological performance, enhanced the delayed survival of newborn neurons in the dentate gyrus and subventricular zone, and stimulated angiogenesis in the striatal ischemic penumbra, but not the dentate gyrus. We conclude that in the ischemic brain VEGF exerts an acute neuroprotective effect, as well as longer latency effects on survival of new neurons and on angiogenesis, and that these effects appear to operate independently. VEGF may, therefore, improve histological and functional outcome from stroke through multiple mechanisms.

Postischemic Gene Transfer of Soluble Flt-1 Protects against Brain Ischemia with Marked Attenuation of Blood—Brain Barrier Permeability

“…Although stimulation of VEGF receptors on either luminal or abluminal side by different administration routes may lead to differences in signaling pathways in angiogenesis, intravenous (Zhang et al, 2000), intra-arterial (Abumiya et al, 2005), or intraventricular (Sun et al, 2003) administration of VEGF promotes angiogenesis in ischemic brain, suggesting that the delivery route of VEGF is not essential for angiogenesis. In the above studies, late administrations of VEGF (a couple days after ischemia) provoked augmentation of angiogenesis (Zhang et al, 2000;Sun et al, 2003). Because the gene transfer of sFlt-1 Macrophage/ monocyte infiltrations were significantly reduced in AdsFlt-1 (n = 9) versus AdlacZ (n = 9) group.…”

Neurovascular Protection by Targeting Early Blood–Brain Barrier Disruption with Neurotrophic Factors after Ischemia–Reperfusion in Rats

“…32 Vascular hyperpermeability is intricately associated with and is inherent to progressive pathologic angiogenesis, marked by leaky vessels and increased permeability to macromolecules and water, and resulting in an uncontrolled delivery of solutes to the tissue. 33 A wealth of data indicates PEDF as an inhibitor of vascular permeability and angiogenesis.…”

Atorvastatin Induction of VEGF and BDNF Promotes Brain Plasticity after Stroke in Mice

“…Vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) are two important neurotrophic factors that have multiple effects on sustaining and evoking elements of brain plasticity (Jin et al, 2002;Sun et al, 2003). Vascular endothelial growth factor is an angiogenic agent, which promotes neurogenesis and stem-progenitor cell migration (Jin et al, 2002;Sun et al, 2003).…”

“…Vascular endothelial growth factor is an angiogenic agent, which promotes neurogenesis and stem-progenitor cell migration (Jin et al, 2002;Sun et al, 2003). Likewise, BDNF regulates neuronal survival, cell migration, and synaptic function (Aguado et al, 2003;Gorski et al, 2003).…”