Angiopoietin-1 reduces cerebral blood vessel leakage and ischemic lesion volume after focal cerebral embolic ischemia in mice

Zhang, Z.G; Zhang, L; Croll, Susan D.; Chopp, Michael

doi:10.1016/s0306-4522(02)00175-6

Cited by 154 publications

(122 citation statements)

References 24 publications

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“…Furthermore, according to the permeability properties of VEGF, we observed that this factor exacerbates ischemic edema and enhances trans-endothelial sucrose transport on an in vitro BBB model placed in ischemic mimicking conditions (OGD). However, we showed that a coadministration of Ang-1 blocked not only the VEGF-induced BBB permeability as similarly reported (Zhang et al, 2002b) but also the VEGF-induced ischemic damage. These results raised the question of whether VEGF and Ang-1 have direct or indirect effects on the infarcted tissue.…”

Section: Discussionsupporting

confidence: 90%

VEGF-Induced BBB Permeability is Associated with an MMP-9 Activity Increase in Cerebral ischemia: Both Effects Decreased by ANG-1

Valable

Montaner

Bellail

et al. 2005

J Cereb Blood Flow Metab

175

125

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After cerebral ischemia, angiogenesis, by supplying for the deficient perfusion, may be a beneficial process for limiting neuronal death and promoting tissue repair. In this study, we showed that the combination of Ang-1 and vascular endothelial growth factor (VEGF) provides a more adapted therapeutic strategy than the use of VEGF alone. Indeed, we showed on a focal ischemia model that an early administration of VEGF exacerbates ischemic damage, because of its effects on bloodbrain barrier (BBB) permeability. In contrast, a coapplication of Ang-1 and VEGF leads to a significant reduction of the ischemic and edema volumes by 50% and 42%, respectively, in comparison with VEGF-treated mice. We proposed that Ang-1 blocks the BBB permeability effect of VEGF in association with a modulation of matrix metalloproteinase (MMP) activity. Indeed, we showed on both ischemic in vivo and BBB in vitro models that VEGF enhances BBB damage and MMP-9 activity and that Ang-1 counteracts both effects. However, we also showed a synergic angiogenic effect of Ang-1 and VEGF in the brain. Taken together, these results allow to propose that, in cerebral ischemia, the combination of Ang-1 and VEGF could be used early to promote the formation of mature neovessels without inducing side effects on BBB permeability.

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Section: Discussionsupporting

confidence: 90%

VEGF-Induced BBB Permeability is Associated with an MMP-9 Activity Increase in Cerebral ischemia: Both Effects Decreased by ANG-1

Valable

Montaner

Bellail

et al. 2005

J Cereb Blood Flow Metab

175

125

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“…Thus Ang-1 therapy may have therapeutic potential in reducing BBB breakdown and the ensuing edema after massive brain injury. In this context it is interesting that a recent study reports reduction in BBB leakage to Evans blue and a reduction in infarct volume in mice injected with a recombinant adenovirus expressing Ang-1 before middle cerebral artery (MCA) occlusion (Zhang et al, 2002a). …”

Section: Endothelial Ang-1 and Ang-2 During Bbb Breakdownmentioning

confidence: 99%

Altered Expression of Angiopoietins During Blood-Brain Barrier Breakdown and Angiogenesis

Nourhaghighi

Teichert-Kuliszewska

Davis

et al. 2003

Laboratory Investigation

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SUMMARY:Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) belong to a novel family of endothelial growth factors that function as ligands for the endothelial-specific receptor tyrosine kinase, Tie-2. Ang-1 reduces endothelial permeability of noncerebral vessels and has a major role in vascular stabilization and maturation, whereas Ang-2 is thought to be an endogenous antagonist of the action of Ang-1 at Tie-2. Expression of these ligands at the mRNA and protein level were studied during both blood-brain barrier (BBB) breakdown and cerebral angiogenesis occurring in the rat cortical cold-injury model by RT-PCR analysis and immunohistochemistry respectively, during a time course of 6 hours to 6 days. In addition, immunohistochemical detection of fibronectin was used to detect BBB breakdown at the lesion site and dual labeling was used to determine whether the vessels demonstrating BBB breakdown expressed endothelial Ang-1 or Ang-2. Endothelial Ang-1 and Tie-2 proteins were present in all cerebral vessels of normal brain including those of the choroid plexuses, whereas both these proteins as well as Ang-2 were present in choroid plexus epithelium and in ependymal cells, suggesting that angiopoietins have an autocrine effect on these cell types as well. In contrast, in the early phase after injury during the known period of BBB breakdown, increased Ang-2 mRNA and protein and decreased endothelial Ang-1 and Tie-2 proteins were observed. Two to 6 days after injury, the progressive increase in Ang-1 mRNA and protein and the decrease in Ang-2 coincided with cerebrovascular angiogenesis. Confocal microscopy showed colocalization of both Ang-1 and Ang-2 in endothelium of lesion vessels, and our observation of colocalization of Ang-1 and Ang-2 in polymorphonuclear leukocytes and macrophages has not been reported previously. This study demonstrates that Ang-1 is an important factor in maintaining normal homeostasis in the brain. Thus Ang-1 therapy may have therapeutic potential in reducing BBB breakdown and the ensuing edema after massive brain injury. (Lab Invest 2003, 83:1211-1222.

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“…In addition, Ang-1 has neuroprotective effect as well. Its receptor, called Tie-2, can be found on endothelial cells, pericytes, and neuronal cells [206][207][208][209][210][211]. To assess the impact of Ang-1 on the HT process 4 different groups of rats were observed.…”

Section: Ang-1mentioning

confidence: 99%

Hemorrhagic transformation of ischemic stroke

J¹,

Hortobágyi²

2017

Vascul Dis Ther

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The better understanding of the diverse mechanisms leading to the hemorrhagic transformation of an ischemic stroke is the crucial point in the prevention of this altogether common phenomenon. The different individual risk factors include the anatomical variability of collateral blood supply, age, genetics, body weight, etiology of the occlusion, side of the occluded vessel, renal status, stroke severity, history of high serum glucose or hypertension and hypertension or hyperglycemia at the onset of the stroke, ferritin level, INR, antiplatelet usage or the platelet count etc. All these might contribute to the process of hemorrhagic transformation. These risk factors have been identified by retrospective epidemiological studies and are useful to identify patients who are at high risk for hemorrhagic conversion and help the decision between conservative, thrombolytic or more advanced treatments such as thrombectomy. The modulations of potential molecular targets participating in the process seem to be promising in animal models, but human trials are lacking the breakthrough success so far, both in extending the time frame of the thrombolysis and in replacing the recombinant tissue plasminogen activator (rtPA) as thrombolytic agent.So far, the careful preselection of patients eligible for thrombolytic therapy is the best way to prevent hemorrhagic transformation. The intensive research in the field revealing small but important molecular details are continuously contributing to the better understanding of hemorrhagic transformation with the intention of finding new agents that co-administrated to the rtPA or completely replacing that could decrease the risk of secondary bleeding.The aim of this review is to give comprehensive insight into the process of hemorrhagic transformation of ischemic stroke, starting with basic overview of the penumbra concept and the collateral supply followed by discussion of the recanalisation-reperfusion-hemorrhagic transformation process after vessel occlusion also highlighting the importance of timing and ratio of recanalisation spontaneously and in case of thrombolytic agent administration. We overview the risk factors of hemorrhagic transformation, which may be helpful to physicians to identify high risk patients before rtPA administration. The last part of the work is dealing with future therapeutic possibilities based on the so far revealed molecular mechanisms of hemorrhagic transformation. With the aim to assess the rate and influencing factors on the recanalisation and reperfusion rate 381 patients with large-vessel occlusion was investigated. The patient group involved ones treated with rtPA or treated conservatively. Partial or complete recanalisation was achieved in 121 out of 210 (58%) patients after intravenous rtPA administration. The recanalisation success was more likely if the patient had atrial fibrillation [4] -maybe because cardioembolic clots consists more fibrin and are more likely to reopen by plasmin proteolysis than thrombosis of an atherosclerotic plaq...

show abstract

Angiopoietin-1 reduces cerebral blood vessel leakage and ischemic lesion volume after focal cerebral embolic ischemia in mice

Cited by 154 publications

References 24 publications

VEGF-Induced BBB Permeability is Associated with an MMP-9 Activity Increase in Cerebral ischemia: Both Effects Decreased by ANG-1

VEGF-Induced BBB Permeability is Associated with an MMP-9 Activity Increase in Cerebral ischemia: Both Effects Decreased by ANG-1

Altered Expression of Angiopoietins During Blood-Brain Barrier Breakdown and Angiogenesis

Hemorrhagic transformation of ischemic stroke

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