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Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo
Open accessAbstract
Modulation of Tie2 receptor activity by its angiopoietin ligands is crucial for angiogenesis, blood vessel maturation, and vascular endothelium integrity. It has been proposed that angiopoietins 1 (Ang1) and 2 (Ang2) are pro- and anti-angiogenic owing to their respective agonist and antagonist signaling action through the Tie2 receptor. The function of Ang2 has remained controversial, however, with recent reports suggesting that in some circumstances, it may be pro-angiogenic. We have examined this issue using the transient ocular microvessel network called the pupillary membrane as a unique in vivo model for studying the effects of vascular regulators. We show that in vivo , in the presence of endogenous vascular endothelial growth factor (VEGF)-A, Ang2 promotes a rapid increase in capillary diameter, remodeling of the basal lamina, proliferation and migration of endothelial cells, and stimulates sprouting of new blood vessels. By contrast, Ang2 promotes endothelial cell death and vessel regression if the activity of endogenous VEGF is inhibited. These observations support a model for regulation of vascularity where VEGF can convert the consequence of Ang2 stimulation from anti- to pro-angiogenic.
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“in the presence of VEGF, Ang-2 can prime vessels to mount a robust pro-angiogenic response (89)”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [89]
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Serum levels of angiopoietin-2 are associated with the growth of multiple myeloma
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BackgroundExpression and Localization of Angiogenic Growth Factors in Developing Porcine Mesonephric Glomeruli
Spiegelaere, W. D., Cornillie, P., Erkens, T., Denis, V. L., Casteleyn, C. R., Poucke, M. V., Burvenich, C., Luc, V. H., Ginneken, C. J. V., Peelman, L. J., et al. (2010) · Journal of Histochemistry & Cytochemistry · doi:10.1369/jhc.2010.956557 · Cited by 15
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“It has previously been shown that Ang-2 destabilises vessel walls and promotes vessel regression in the absence of VEGF or vessel sprouting in the presence of VEGF (Maisonpierre et al., 1997; Lobov et al., 2002).”
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“However, when VEGF is present, Ang-2 has a marked angiogenic effect (19).”
Background1,3,5-Triazine Analogs: A Potent Anticancer Scaffold
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“There is evidence that Ang-1 induces endothelial cell sprouting (17), that its overexpression increases vascularization in mice (15), and that tie-1 and tie-2 regulate intussusceptive microvascular growth (18).”
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“In contrast, Ang-2, by exerting an antagonistic action on the Ang-1/Tie-2 receptor signal, causes vessel destabilization, loosening of the vessel wall, and suppression of endothelial cell contact with peri-endothelial mural cells rendering endothelial cells more accessible to VEGF, potentially to further promote angio…”
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“The solution of the above network evolvability e0 of linear biological network (9) in carcinogenesis can be obtained by decreasing e until no positive solution P in (25) within 0 , P # eI in (27).”
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“However, in the absence of VEGF, Ang2 leads to vessel regression and endothelial cell death [39].”
BackgroundAngiopoietin 2 expression in the cornea and its control of corneal neovascularisation
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“As representatives of angiopoietins, Ang‐1 and Ang‐2 are chosen to elucidate the vascular maturation and dynamics in response to angiopoietins (Baffert et al., 2004; Korhonen et al., 2016; Lobov et al., 2002; Reiss, 2010).”
Background5′-(N-ethylcarboxamido) adenosine improves angiogenesis in transplanted human ovarian tissue
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“Whether ANGPT2 acts pro- or antiangiogenic also depends on the presence of other angiogenic factors, notably VEGFA [51,55,56].”
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HIV-based vectors and angiogenesis following rabbit hindlimb ischemia1
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“pro-angiogenic effects, whereas when VEGF was inhibited Ang-2 promoted endothelial cell death and vessel regression [40].”
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“Therefore, it is clear that any evaluation of Ang-2/Ang-1 participation in injury should also consider how VEGF levels are affected (Lobov et al. 2002).”
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Uncovering a Key Role of ETS1 on Vascular Abnormality in Glioblastoma
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“Bevacizumab, a humanized antivascular endothelial growth factor (anti-VEGF) neutralizing antibody, has been approved for recurrent GBM by FDA but has not led to improved overall survival (13).”
BackgroundInfluentialFadakar, K., Rahmani, S., Tedeschi, T. R., Lavine, J. A., & Fawzi, A. A. (2024) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.65.4.37 · Cited by 11
“46,47 Because we observed a decrease in the expression of ANGPT2 in endothelial cells, and no alteration of ANGPT1 in either compartment, it is plausible that IVB tips the balance toward a higher ANGPT1/ANGPT2 ratio, improving vessel stabilization.”
Increased intravitreal angiopoietin-2 levels associated with rhegmatogenous retinal detachment
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“Ang-2 is known to sensitize retinal vasculature to VEGF, but in the absence of VEGF, Ang-2 rather induces apoptosis of ECs and blood vessel regression [39], which could be relevant in eyes with RRD with increased Ang-2 and relatively low VEGF levels.”
BackgroundInfluentialNeural regulation of CNS angiogenesis during development
Ma, S., & Huang, Z. (2014) · Frontiers in Biology · doi:10.1007/s11515-014-1331-y · Cited by 12
“…a brain endothelial cell specific Cre driver show that Smad4 deletion from EC causes impaired physical association between pericytes and brain endothelial cells, suggesting that TGFβ/BMP ligands (presumably secreted and processed by neural cells) tightly control such interactions (Li et al., 2011).”
BackgroundAngiopoietin-2/Tie2 Signaling Involved in TNF-α Induced Peritoneal Angiogenesis
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“Studies have already shown that VEGF may promote angiogenesis as well as up-regulate expression of Ang2 both in vitro and in vivo (20, 21).”
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“Furthermore, the presence of high concentrations of Ang2 destabilize existing vessels by diminishing the production of ECs, a phenomenon that is inhibited by Ang1, which contributes in stabilizing vessels and promoting the production of endothelial cells [67,68].”
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“Both Angiopoietin-2 and VCAM induce vascular permeability by pericyte loss, which leads to the disruption of the vascular barrier integrity [3,8,9].”
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“Normally, Ang-2 binds to its receptor Tie2 and promotes the proliferation of vascular endothelial cells to form new blood vessels in the presence of VEGF (71).”
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“This release removes the quiescent control of ANGPT1 on endothelial cells and induces vessel sprouting 65,67,68 .”
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Vasculogenesis and Angiogenesis
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“The present findings suggest that ANGPTL4 displays VEGF-dependent activity reminiscent of the outcome of Ang-2 in the presence or absence of VEGF-A [27].”
Background
Metadata
- Authors
- Lobov, I. B., Brooks, P. C., & Lang, R. A.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Lang, Richard A.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2002-08-05
- Volume
- 99
- Issue
- 17
- Pages
- 11205-11210
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC123234
- OpenAlex
- W2113920157
- Semantic Scholar
- 60029f2ec9a0f8c30ad5b2536f206fc2cbab3666
- Cited by
- 676
- References
- 30
- Citations by year
- 2026: 10 · 2025: 23 · 2024: 32 · 2023: 20 · 2022: 31 · 2021: 23 · 2020: 14 · 2019: 24 · 2018: 21 · 2017: 16 · 2016: 25 · 2015: 34 · 2014: 29 · 2013: 37 · 2012: 35
- FWCI
- 10.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- International Retinal Research Foundation
- National Institutes of Health (5r01ey012370-05)
- National Eye Institute (R01EY014102, R01 EY12370, R01EY011234, R01EY010559)
- National Cancer Institute (R01CA091645)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- angiopoietin-2, angiopoietin-1, Tie2 receptor, VEGF-A, angiogenesis, capillary structure, endothelial cell survival, endothelial cell death, vessel regression, endothelial cell proliferation, endothelial cell migration, capillary diameter, pupillary membrane, ocular microvasculature
- MeSH terms
- Animals, Capillaries, Cell Division, Cornea, Endothelium, Vascular, Enzyme Inhibitors, Humans, Lymphokines, Muscle, Smooth, Vascular, Proteins, Recombinant Proteins, Endothelial Growth Factors, Rats, Sprague-Dawley, Apoptosis, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A, Angiopoietin-2, Rats
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