The Janus Face of VEGF in Stroke (original) (raw)
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VEGF expression in human brain tissue after acute ischemic stroke
Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie, 2011
Ischemic stroke is the third most common cause of death in humans, requiring further studies to elucidate its pathophysiological background. One potential mechanism to increase oxygen delivery to the affected tissue is induction of angiogenesis. The most potent proangiogenic factor is VEGF. For this reason, our study investigated immunohistochemically VEGF reactivity in different cellular brain compartments from 15 ischemic stroke patients, as well as from 2 age control cases. By enzymatic immunohistochemistry, we investigate VEGF expression in different brain cell compartments and then we quantified its signal intensity by assessing integrated optical densities (IOD). To establish the exact cellular brain topography of VEGF immunoreactivity we performed double fluorescent immunohistochemistry series (VEGF÷NeuN, GFAP, CD68, CD105). In control samples, VEGF reactivity was observed especially in neurons from the Brodmann cortical layers IV to VI and in protoplasmic astrocytes from the...
Effects of vascular endothelial growth factor in ischemic stroke
Journal of Neuroscience Research, 2012
Vascular endothelial growth factor (VEGF) is a pleiotropic growth factor that is crucially involved in neurovascular remodeling in the ischemic brain. VEGF promotes angiogenesis, protects ischemic neurons from injury, has potent anti-inflammatory actions, and promotes brain plasticity, in addition to enhancing the recruitment and proliferation of neural precursor cells. These broad actions make VEGF interesting as a model molecule that allows understanding endogenous responses of the brain to injuries. However, several studies indicate that the route and timing of VEGF administration are crucial for the effects of VEGF on ischemic brain tissue. Hence, systemic VEGF delivery in the very acute stroke phase may exacerbate brain damage because of the promotion of blood-brain barrier breakdown that inevitably accompanies vascular growth. Future studies aimed at the promotion of neurovascular remodeling in ischemic stroke should carefully take into consideration pleiotropic actions of angiogenic growth factors beyond vascular growth. V
Vascular and neuronal effects of VEGF in the nervous system: implications for neurological disorders
Seminars in Cell & Developmental Biology, 2002
Vascular endothelial growth factor (VEGF) was originally discovered as an endothelial-specific growth factor. While the predominant role of this growth factor in the formation of new blood vessels (angiogenesis) is unquestioned, recent observations indicate that VEGF also has direct effects on neurons and glial cells, and stimulates their growth, survival and axonal outgrowth. Because of these pleiotropic effects, VEGF has now been implicated in several neurological disorders both in the preterm infant (leukomalacia) and the adult (stroke, neurodegeneration, cerebral and spinal trauma, ischemic and diabetic neuropathy, nerve regeneration). A challenge for the future is to unravel to what extent the effect of VEGF in these disorders relates to its angiogenic activity or direct neurotrophic effect.
VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia
Journal of Clinical Investigation, 2003
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. Conflict of interest: The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: middle cerebral artery occlusion (MCAO); external carotid artery (ECA); middle cerebral artery (MCA); artificial cerebrospinal fluid (aCSF); doublecortin (Dcx); dentate gyrus (DG); subgranular zone (SGZ); subventricular zone (SVZ).
Journal of Cerebral Blood Flow & Metabolism, 2005
Delayed administration of vascular endothelial growth factor (VEGF) promotes functional recovery after focal cerebral ischemia. However, early intravenous injection of VEGF increases blood–brain barrier (BBB) leakage, hemorrhagic transformation and infarct volume whereas its application to cortical surface is neuroprotective. We have investigated whether or not early intracerebroventricular administration of VEGF could replicate the neuroprotective effect observed with topical application and the mechanism of action of this protection. Mice were subjected to 90 mins middle cerebral artery (MCA) occlusion and 24 h of reperfusion. Vascular endothelial growth factor (8 ng, intracerebroventricular) was administered 1 or 3 h after reperfusion. Compared with the vehicle-treated (intracerebroventricular) group, VEGF decreased the infarct volume along with BBB leakage in both treatment groups. Neurologic disability scores improved in parallel to the changes in infarct volume. Independently ...
Open Access Macedonian Journal of Medical Sciences, 2019
BACKGROUND: Glucose and oxygen supply to neurons are disrupted during acute ischemic stroke, resulting in hypoxia. This event, in turn, activates the transcription of hypoxia-inducible factor (HIF-1), which is responsible for activating genes responsible for angiogenesis, including vascular endothelial growth factor (VEGF). VEGF and their receptor systems exert complex mechanisms of angiogenesis, including the stimulator, inhibitors, angiogenic and modulator. VEGF-A is the primary regulator of angiogenesis, both during physiological and pathological conditions. Nevertheless, the role of VEGF on the prognosis of hypoxia remains controversial. AIM: The purpose of this study was to address if there is any difference between the mean expression of VEGF-A between acute ischemic patients and non-ischemic stroke subjects. METHODS: This was an observational study with a cross-sectional design, the population in this research is the acute ischemic stroke patients and non-ischemic stroke subj...
Translational Stroke Research, 2022
The breakdown of the blood–brain barrier (BBB) is a critical event in the development of secondary brain injury after stroke. Among the cellular hallmarks in the acute phase after stroke are a downregulation of tight-junction molecules and the loss of microvascular pericyte coverage and endothelial sealing. Thus, a rapid repair of blood vessel integrity and re-stabilization of the BBB is considered an important strategy to reduce secondary brain damage. However, the mechanisms underlying BBB disruption remain poorly understood. Especially, the role of VEGF in this context remains inconclusive. With the conditional and reversible VEGF expression systems, we studied the time windows of deleterious and beneficial VEGF actions on blood vessel integrity in mice. Using genetic systems for gain of function and loss of function experiments, we activated and inhibited VEGF signaling prior and simultaneously to ischemic stroke onset. In both scenarios, VEGF seems to play a vital role in conta...
Journal of Cerebral …, 2002
In an effort to elucidate the molecular mechanisms underlying cerebral vascular alteration after stroke, the authors measured the spatial and temporal profiles of blood-brain barrier (BBB) leakage, angiogenesis, vascular endothelial growth factor (VEGF), associated receptors, and angiopoietins and receptors after embolic stroke in the rat. Two to four hours after onset of ischemia, VEGF mRNA increased, whereas angiopoietin 1 (Ang 1) mRNA decreased. Three-dimensional immunofluorescent analysis revealed spatial coincidence between increases of VEGF immunoreactivity and BBB leakage in the ischemic core. Two to 28 days after the onset of stroke, increased expression of VEGF/VEGF receptors and Ang/Tie2 was detected at the boundary of the ischemic lesion. Concurrently, enlarged and thin-walled vessels were detected at the boundary of the ischemic lesion, and these vessels developed into smaller vessels via sprouting and intussusception. Threedimensional quantitative analysis of cerebral vessels at the boundary zone 14 days after ischemia revealed a significant (P < 0.05) increase in numbers of vessels (n ס 365) compared with numbers (n ס 66) in the homologous tissue of the contralateral hemisphere. Furthermore, capillaries in the penumbra had a significantly smaller diameter (4.8 ± 2.0 m) than capillaries (5.4 ± 1.5 m) in the homologous regions of the contralateral hemisphere. Together, these data suggest that acute alteration of VEGF and Ang 1 in the ischemic core may mediate BBB leakage, whereas upregulation of VEGF/VEGF receptors and Ang/Tie2 at the boundary zone may regulate neovascularization in ischemic brain.