Angiopoietin-2 is Vasoprotective in the Acute Phase of Cerebral Ischemia

Marteau, Léna; Valable, Samuel; Divoux, Didier; Roussel, Simon; Touzani, Omar; MacKenzie, Eric T.; Bernaudin, Myriam; Petit, Edwige

doi:10.1038/jcbfm.2012.178

Cited by 13 publications

(11 citation statements)

References 42 publications

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“…Ang-2 is known to induce pericyte loss and destabilize blood vessels 57,58 ; however, the role of Ang2 in vascular integrity and permeability remains controversial. Previous work suggests that Ang-2 reduced BBB permeability after stroke 59 and induced vessel stabilization in glioma, 60 and that mice deficient in Ang-2 exhibited defects in pericyte in lymphatic vessels. 61 Here we observed that overexpression of Ang-2 in Adamts13 2/2 mice increased pericyte coverage and reduced vascular damage; these apparent differences might be due to the different models used in the various studies.…”

Section: Discussionmentioning

confidence: 96%

RETRACTED: ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery

Cao

Yang

et al. 2017

Blood

102

100

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Key Points• ADAMTS13 controls key steps of vascular remodeling during stroke recovery.• Recombinant ADAMTS13 enhances ischemic neovascularization and vascular repair.Angiogenic response is essential for ischemic brain repair. The von Willebrand factor (VWF)-cleaving protease disintegrin and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) is required for endothelial tube formation in vitro, but there is currently no in vivo evidence supporting a function of ADAMTS13 in angiogenesis. Here we show that mice deficient in ADAMTS13 exhibited reduced neovascularization, brain capillary perfusion, pericyte and smooth muscle cell coverage on microvessels, expression of the tight junction and basement membrane proteins, and accelerated blood-brain barrier (BBB) breakdown and extravascular deposits of serum proteins in the peri-infarct cortex at 14 days after stroke. Deficiency of VWF or anti-VWF antibody treatment significantly increased microvessels, perfused capillary length, and reversed pericyte loss and BBB changes in Adamts13 2/2 mice. Furthermore, we observed that ADAMTS13 deficiency decreased angiopoietin-2 and galectin-3 levels in the isolated brain microvessels, whereas VWF deficiency had the opposite effect. Correlating with this, overexpression of angiopoietin-2 by adenoviruses treatment or administration of recombinant galectin-3 normalized microvascular reductions, pericyte loss, and BBB breakdown in Adamts13 2/2 mice. The vascular changes induced by angiopoietin-2 overexpression and recombinant galectin-3 treatment in Adamts13 2/2 mice were abolished by the vascular endothelial growth factor receptor-2 antagonist SU1498. Importantly, treating wild-type mice with recombinant ADAMTS13 at 7 days after stroke markedly increased neovascularization and vascular repair and improved functional recovery at 14 days. Our results suggest that ADAMTS13 controls key steps of ischemic vascular remodeling and that recombinant ADAMTS13 is a putative therapeutic avenue for promoting stroke recovery. (Blood. 2017;130(1):11-22)

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Section: Discussionmentioning

confidence: 96%

RETRACTED: ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery

Cao

Yang

et al. 2017

Blood

102

100

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“… 29 On the contrary, the angiogenic factor Ang2 decreases BBB leakage. 30 Thus, increased levels of VEGF and PlGF, and decreased levels of Ang2, may concur to produce BBB dysfunction and neuronal toxicity in the affected brain regions. Accordingly, we found strong correlations between the CSF levels of NFL (a marker of axonal degeneration) and angiogenesis biomarkers in patients with PD.…”

Section: Discussionmentioning

confidence: 99%

Increased CSF biomarkers of angiogenesis in Parkinson disease

Lindqvist²,

et al. 2015

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Objective:To study biomarkers of angiogenesis in Parkinson disease (PD), and how these are associated with clinical characteristics, blood–brain barrier (BBB) permeability, and cerebrovascular disease.Methods:In this cross-sectional analysis, 38 elderly controls and 100 patients with PD (82 without dementia and 18 with dementia) were included from the prospective Swedish BioFinder study. CSF samples were analyzed for the angiogenesis biomarkers vascular endothelial growth factor (VEGF); its receptors, VEGFR-1 and VEGFR-2; placental growth factor (PlGF); angiopoietin 2 (Ang2); and interleukin-8. BBB permeability, white matter lesions (WMLs), and cerebral microbleeds (CMB) were assessed. CSF angiogenesis biomarkers were also measured in 2 validation cohorts: (1) 64 controls and 87 patients with PD with dementia; and (2) 35 controls and 93 patients with neuropathologically confirmed diagnosis of PD with and without dementia.Results:Patients with PD without dementia displayed higher CSF levels of VEGF, PlGF, and sVEGFR-2, and lower levels of Ang2, compared to controls. Similar alterations in VEGF, PlGF, and Ang2 levels were observed in patients with PD with dementia. Angiogenesis markers were associated with gait difficulties and orthostatic hypotension as well as with more pronounced BBB permeability, WMLs, and CMB. Moreover, higher levels of VEGF and PlGF levels were associated with increased CSF levels of neurofilament light (a marker of neurodegeneration) and monocyte chemotactic protein–1 (a marker of glial activation). The main results were validated in the 2 additional cohorts.Conclusions:CSF biomarkers of angiogenesis are increased in PD, and they are associated with gait difficulties, BBB dysfunction, WMLs, and CMB. Abnormal angiogenesis may be important in PD pathogenesis and contribute to dopa-resistant symptoms.

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“…Angiopoietin 1 (Ang1) opposes the VEGF-induced de-differentiation of BECs (6,7), but its effects on BECs early after ischemia are impeded by a rapid release of angiopoietin 2 (Ang2) (8), which acts as an antagonist of the Ang1 receptor (9). However, an in vivo study also showed that locally applied Ang2 reduced vascular permeability after brain ischemia in mice (10). Ischemia also activates resident microglia that transform into the M2 phenotype early after an ischemic event (11).…”

Section: Introductionmentioning

confidence: 99%