Vascular endothelial growth factor gene expression in middle cerebral artery occlusion in the rat (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...
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 …, 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.
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
Gene Therapy, 2007
Background and Purpose-Exogenous delivery of vascular endothelial growth factor gene (VEGF) may provide a useful approach to the treatment of brain ischemia. We investigated the use of a hypoxia-responsive element to control VEGF expression given for neuroprotection. Methods-Three groups (nϭ36) of mice received AAVH9-VEGF, AAVH9-lacZ, or saline injection. Five days after gene transfer, the mice underwent 45 minutes of transient middle cerebral artery occlusion (tMCAO) followed by 1 to 7 days of reperfusion. Infarct volume was determined using cresyl violet staining; neuronal injury was examined using TUNEL, cleaved caspase-3, and fluoro-Jade B staining. Results-Hypoxia-inducible factor-1 (HIF-1) was overexpressed after tMCAO in the ischemic hemisphere in the brain. Expression of lacZ, mediated by AAV-lacZ, was seen before and after tMCAO; however, AAVH9-lacZ-mediated lacZ expression was detected only after tMCAO. Infarct volume was smaller in the AAVH9-VEGF-transduced group compared with AAVH9-lacZ and saline groups (55% reduction, PϽ0.05) with reduced TUNEL (29Ϯ5% and 30Ϯ7% versus 12Ϯ3%, PϽ0.05), cleaved caspase-3 (20Ϯ3% and 21Ϯ5% versus 13Ϯ4%, PϽ0.05) and fluoro-Jade B (23Ϯ3% and 24Ϯ5% versus 12Ϯ5%, PϽ0.05)-positive neurons, respectively. Conclusion-Exogenous expression of VEGF through AAVH9-VEGF gene transfer 5 days before the onset of ischemia provides neuroprotection. Hypoxia-responsive element is a viable strategy of restricting VEGF expression to areas of ischemia to minimize adverse effects of therapy on adjacent normal parenchyma.
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 ...
Transforming growth factor-β1 exhibits delayed gene expression following focal cerebral ischemia
Brain Research Bulletin, 1995
Transfmlning growth factor-~l (TGF-pl) is a pleiotropic peptide growth factor. The expression of TGF-pl mRNA in the focal ~ cortex of rats was studied by means of Nornw, h,~xk~tim. A modmt~ k)w k,~ of c(mt~,v~ expressed TGF-~I1 mRNA was det~tml following sham-surgery or in the co.;iidalafal (nmgschemic) cortex. A idgnifi~nt inoremm of TGF-/ll mRNA Iovel in the ischemic cortox was ob-~ed at 2 days (&2-tokl k.:me~ =~.pared to dmn-opormd animlds, p < 0.01, n = 4) folBowing permanent occlusion of Ule middle cerebral artmy (PMCAO). The elevabld TGF~I1 mRNA expression was plateaued for up to 15 days (3.6-told increase, p < 0.01) following PMCAO. This m profile for TGF-~I mRNA exlxeasion in focal stroke was signiflcanUy delayed compared to that of TNF-a, IL-lp and IL-6 mRNA eXlXassions as demonslbrated prevlomdy which peaked at 12 h and deceeased to aknost basa lewas by S dws falowing PMeAO. Wcmmnngly. the TGF-,81 mRNA exlx'oeaton profile was mmmtudl~ parallel with that of monocyte/~ a~:tamdation in the ischemic cortex, as well as with the increased formation of exll~-ceUular matdx in the focal ischemtc bra~ Thase data suggast that TGF-/I1 may ptay a role in anti-inflammatory process and in tissue remodeling following ischemic brain injury.