Correlation of VEGF and Angiopoietin Expression with Disruption of Blood–Brain Barrier and Angiogenesis after Focal Cerebral Ischemia

Zhang, Zheng Gang; Zhang, Li; Tsang, Wayne; Soltanian‐Zadeh, Hamid; Morris, Daniel C.; Zhang, Ruilan; Goussev, Anton; Powers, Cecylia; Yeich, Thomas; Chopp, Michael

doi:10.1097/00004647-200204000-00002

Cited by 373 publications

(315 citation statements)

References 57 publications

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“…The present study confirms observations of microvessel hyperdensities in the ischemic infarction zone (Manoonkitiwongsa et al, 2001a) and is consistent with previous studies that indicate that angiogenesis induced by ischemia is not a widespread reaction of parenchymal microvessels in the entire ischemic zone distal to MCA occlusion (Marti et al, 2000;Zhang et al, 2000Zhang et al, , 2002. This is reminiscent of the localized angiogenesis observed after myocardial infarct where it has been postulated that a spatially restricted pattern of thrombospondin-1 in the infarct margin limits the spread of both ischemic inflammation and angiogenesis (Frangogiannis et al, 2005).…”

Section: Discussionsupporting

confidence: 92%

Stroke-Evoked Angiogenesis Results in a Transient Population of Microvessels

Friedman

Cheng

et al. 2007

J Cereb Blood Flow Metab

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The role of angiogenesis after stroke is unclear; if angiogenesis supports long-term recovery of blood flow, then microvessel hyperdensity consequent to angiogenesis should persist in infarcted cortex. Here, we assess the long-term stability of ischemia-induced microvessels after 2-h transient rat middle cerebral artery occlusion (tMCAo) followed by 30, 90, or 165 days of reperfusion. Stereological measures of microvessel density were taken adjacent to and within cortical cysts. Vascular permeability was documented by extravasation of immunoglobulin (IgG) and of fluorescein-dextran. After 30 days reperfusion, a significantly increased microvessel volume density (V V ) was restricted to the inner margin of cystic infarcts as compared with the region external to the infarct or contralateral control cortex (F = 42.675, P < 0.001). The hyperdense ischemic vasculature was abnormally leaky to IgG and fluorescein-dextran. Between 30 and 90 days of reperfusion, this vessel hyperdensity regressed significantly and then regressed further but less drastically between 90 and 165 days. Phagocytic macrophages were restricted to the infarct and dynamic changes in their number correlated with microvessel regression. Additional ED-1 labeled inflammatory cells were widely distributed inside and external to the infarct, even after 165 days of reperfusion. These data show that ischemia evoked angiogenesis results, at least in part, in transient populations of leaky microvessels and phagocytic macrophages. This suggests that a major role of this angiogenesis is for the removal of necrotic brain tissue.

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Section: Discussionsupporting

confidence: 92%

Stroke-Evoked Angiogenesis Results in a Transient Population of Microvessels

Friedman

Cheng

et al. 2007

J Cereb Blood Flow Metab

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“…Gliomas express a range of growth factors and cytokines, however VEGF is unique among these growth factors in that it induces VP as well as neovascularization [55][56][57][58]. Intra-cranial administration of recombinant VEGF to mice has been shown to increase VP and result in breakdown of the BBB, however the mechanisms regulating this process remain poorly understood [59][60][61]. Therefore, in this study we have examined Src-deficient mice, which we have previously shown to have a 'leakage-resistant' phenotype in response to VEGF.…”

Section: Discussionmentioning

confidence: 99%

Reduced Glioma Infiltration in Src-deficient Mice

et al. 2006

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SummaryMalignant brain tumors, such as glioblastoma, are characterized by extensive angiogenesis and permeability of the blood-brain barrier (BBB). The infiltration of glioma cells away from the primary tumor mass is a pathological characteristic of glial tumors. The infiltrating tumor cells represent a significant factor in tumor recurrence following surgical debulking, radiation, and chemotherapy treatments. Vascular endothelial growth factor (VEGF)-mediated vascular permeability (VP) has been associated with the progression of glioma tumor growth and infiltration into surrounding normal brain parenchyma. While VEGF induces a robust VP response in control mice (src +/+ or src +/− ), the VP response is blocked in src −/− mice that demonstrate a 'leakage-resistant phenotype' in the brain. We used the Src-deficient mouse model to determine the role of Src in the maintenance of the BBB following orthotopic implantation and growth of glioma cells in the brain. Although solid tumor growth was the same in control and src −/− mice, the infiltrating component of glioma growth was reduced in src −/− mice. Characterization of the expression and localization of the extracellular matrix (ECM) protein fibrinogen was evaluated to determine the effect of a Src-mediated VP defect in the host compartment. These studies indicate that the reduced VP of host brain blood vessels of src −/− mice mediates a reduction in glioma cell invasion in a mouse brain tumor xenograft model.

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“…In rodent stroke, alteration of angiopoietin-1 in the ischemic core mediates BBB disruption whereas angiopoietin-2 regulates neovascularization. 114 In stroke patients, increased blood levels of angiopoietin-1 are associated with tPA-related hemorrhage. 115 High-mobility-group-box-1 is also involved in neurovascular repair after ischemic stroke.…”

Section: Delayed Hemorrhagic Transformationmentioning

confidence: 99%

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

Jickling

Liu

Stamova

et al. 2013

J Cereb Blood Flow Metab

454

369

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Hemorrhagic transformation (HT) is a common complication of ischemic stroke that is exacerbated by thrombolytic therapy. Methods to better prevent, predict, and treat HT are needed. In this review, we summarize studies of HT in both animals and humans. We propose that early HT (o18 to 24 hours after stroke onset) relates to leukocyte-derived matrix metalloproteinase-9 (MMP-9) and brain-derived MMP-2 that damage the neurovascular unit and promote blood-brain barrier (BBB) disruption. This contrasts to delayed HT (418 to 24 hours after stroke) that relates to ischemia activation of brain proteases (MMP-2, MMP-3, MMP-9, and endogenous tissue plasminogen activator), neuroinflammation, and factors that promote vascular remodeling (vascular endothelial growth factor and high-moblity-group-box-1). Processes that mediate BBB repair and reduce HT risk are discussed, including transforming growth factor beta signaling in monocytes, Src kinase signaling, MMP inhibitors, and inhibitors of reactive oxygen species. Finally, clinical features associated with HT in patients with stroke are reviewed, including approaches to predict HT by clinical factors, brain imaging, and blood biomarkers. Though remarkable advances in our understanding of HT have been made, additional efforts are needed to translate these discoveries to the clinic and reduce the impact of HT on patients with ischemic stroke.

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Correlation of VEGF and Angiopoietin Expression with Disruption of Blood–Brain Barrier and Angiogenesis after Focal Cerebral Ischemia

Cited by 373 publications

References 57 publications

Stroke-Evoked Angiogenesis Results in a Transient Population of Microvessels

Stroke-Evoked Angiogenesis Results in a Transient Population of Microvessels

Reduced Glioma Infiltration in Src-deficient Mice

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

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