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.

Apoptosis: Future Targets for Neuroprotective Strategies

“…Intravenous infusion of VEGF within 48 h after the onset of focal ischemia enhances angiogenesis in the penumbra and ameliorates neural recovery [142, 143]. In addition, exogenous administration of VEGF directly administered or overexpressed by gene delivery reduces ischemic brain infarct and decreases cell death [144,145,146,147,148]. Several mechanisms are involved, including modulation of the PI3K/Akt/NFĸB signaling pathway, inhibition of caspase-3 activity, and reduction of apoptosis, as well as modulation of potassium channels [149].…”

VEGF: a critical player in neurodegeneration

“…VEGF may also promote neurogenesis by stimulating ECs to release neurogenic signals, such as brain-derived neurotrophic factor (37). Notably, intracerebroventricular administration of VEGF reduces infarct size, in part by stimulating neurogenesis and angiogenesis (38). Despite this suggestive evidence, there is currently no formal proof that impaired neurogenesis due to low VEGF levels contributes to neurodegeneration.…”

“…VEGF can also have favorable effects on the recovery of an ischemic brain insult. Administration of VEGF via intravenous or intracerebrovascular infusion, or via topical application on the cortex, enhanced angiogenesis in the penumbra and improved neural recovery (44), reduced edema formation and infarct volume (45,46), and amplified neurogenesis (38), while knockdown of VEGF after ischemic stroke enlarged the infarct volume (47). Some caution, however, is warranted, as other studies suggest that delivery of a VEGF trap reduces edema formation and spares ischemic brain tissue (48), while infusion of VEGF induces vascular leakage, with resultant hemorrhagic transformation of the ischemic lesions (44).…”

Vascular endothelial growth factor-B: Impact on physiology and pathology

“…103 Whereas, VEGF-B lacks the undesired adverse angiogenic vitality, 100 consequently it could be regarded as a trophic divisor to reduce effects of neurodegeneration. And, the VEGF-B had no visible neurorestoration effect.…”