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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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“In combination with high levels of VEGF, these effects of Ang2 ready the vessel for the formation of VEGF-induced sprouts [89].”
BackgroundMankhambo, L., Banda, D. L., The IPD Study Group, Jeffers, G., White, S. A., Balmer, P., Nkhoma, S. C., Phiri, H., MOLYNEUX, E. M., Hart, C. A., et al. (2010) · Critical Care · doi:10.1186/cc9025 · Cited by 75
“VEGF and PDGF are working in a complex relation with Ang-1 and Ang-2 to promote endothelial cell survival and to prevent apoptosis [17].”
BackgroundThe dual roles of homeobox genes in vascularization and wound healing
Kachgal, S., Mace, K. A., & Boudreau, N. J. (2012) · Cell Adhesion & Migration · doi:10.4161/cam.22164 · Cited by 72
“ANG2 is also elevated in these cells, which, in conjunction with sustained VEGFA expression, produces a robust angiogenic response.(83) Correspondingly, tumor explants of SkBr3-HOXB7 xenografts revealed greater levels of vascularization than their control counterparts.”
BackgroundSaber, T., Veale, D. J., Balogh, E., McCormick, J., NicAnUltaigh, S., Connolly, M., & Fearon, U. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023540 · Cited by 76
“. Through its receptor Tie-2, Ang2 acts in the presence of abundant VEGF on invading vascular sprouts by blocking the maturation and stabilisation process,”
BackgroundAngiopoietin-2 in experimental colitis
Ganta, V. C., Cromer, W. E., Mills, G. L., Traylor, J. G., Jennings, M. H., Daley, S. K., Clark, B., Mathis, J. M., Bernas, M. J., Boktor, M., et al. (2009) · Inflammatory Bowel Diseases · doi:10.1002/ibd.21150 · Cited by 74
Not just angiogenesis—wider roles for the angiopoietins
Jones, P. F. (2003) · The Journal of Pathology · doi:10.1002/path.1452 · Cited by 77
Thyroid hormone as a regulator of tumor induced angiogenesis
Pinto, M. T., Soares, P., & Ribatti, D. (2010) · Cancer Letters · doi:10.1016/j.canlet.2010.11.011 · Cited by 75
Hepatitis B Virus Promotes Angiopoietin-2 Expression in Liver Tissue
Sanz-Cameno, P., Martín‐Vílchez, S., Lara‐Pezzi, E., Borque, M. J., Salmerón, J., de Rueda, P. M., Solís, J. A., López‐Cabrera, M., & Moreno‐Otero, R. (2006) · American Journal Of Pathology · doi:10.2353/ajpath.2006.051246 · Cited by 76
“ty.(14,15) HCC is a hypervascular tumor that needs the activation of proangiogenic mechanisms, of which Ang2 has been demonstrated to play a central role.”
BackgroundTemporal renal expression of angiogenic growth factors and their receptors in experimental diabetes
Rizkalla, B., Forbes, J. M., Cao, Z., et al. (2005) · Journal of Hypertension · doi:10.1097/00004872-200501000-00026 · Cited by 73
New molecular targets in angiogenic vessels of glioblastoma tumours
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Hepatocellular carcinoma: Where there is unmet need
Bupathi, M., Kaseb, A. O., Meric‐Bernstam, F., et al. (2015) · Molecular Oncology · doi:10.1016/j.molonc.2015.06.005 · Cited by 70
“Finally, pre-clinical studies have shown that Ang2 synergistically augments VEGF-mediated angiogenesis in HCC (Yoshiji et al., 2005; Lobov et al., 2002).”
BackgroundEl‐Asrar, A. M. A., Missotten, L., & Geboes, K. J. (2007) · British Journal of Ophthalmology · doi:10.1136/bjo.2006.109876 · Cited by 70
Plank, M. J., Sleeman, B. D., & Jones, P. F. (2004) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2004.04.012 · Cited by 70
Getting Tie(2)d up in angiogenesis
Ramsauer, M., & D'Amore, P. A. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0217326 · Cited by 70
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“Our results are consistent with prior work showing that Ang2-dependent endothelial cell migration and sprouting of new vessels requires the presence of inflammatory cytokines or VEGF (7, 11).”
BackgroundResultInfluentialSeval, Y., Satı, L., Çelik-Özenci, Ç., et al. (2008) · Placenta · doi:10.1016/j.placenta.2008.06.009 · Cited by 68
Cretu, A., & Brooks, P. C. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21222 · Cited by 67
“Metastatic tumor cells can also bind to fibrinogen/fibrin and regulate tumor cell proliferation and motility (Mosesson, 2005; Lord, 2007).”
BackgroundInfluentialSelf-citationPeroxisome proliferator-activated receptors and angiogenesis
Biscetti, F., Straface, G., Pitocco, D., Zaccardi, F., Ghirlanda, G., & Flex, A. (2009) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2009.04.011 · Cited by 65
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“An in vivo study in an ocular microvascular network has shown that angiopoietin-2 (Ang-2) stimulates new blood vessel formation in the presence of VEGF, but promotes endothelial apoptosis and vessel regression when VEGF levels are low [18].”
BackgroundDrake, J. I., Gomez‐Arroyo, J. G., Dumur, C. I., et al. (2013) · Physiological Genomics · doi:10.1152/physiolgenomics.00166.2012 · Cited by 64
Chade, A., Tullos, N. A., Harvey, T. W., Mahdi, F., & Bidwell, G. L. (2015) · Journal of the American Society of Nephrology · doi:10.1681/asn.2015040346 · Cited by 64
Dell, S., Peters, S., ̈ther, P. M., Kociok, N., & Joussen, A. M. (2006) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.05-1071 · Cited by 65
Holtan, S. G., Verneris, M. R., Schultz, K. R., Newell, L. F., Meyers, G., He, F. C., DeFor, T. E., Vercellotti, G. M., Slungaard, A., MacMillan, M. L., et al. (2015) · Transplantation and Cellular Therapy · doi:10.1016/j.bbmt.2015.02.018 · Cited by 63
“For example, angiopoietin-2 (Ang2) is an AF that can have either pro-angiogenic or antiangiogenic function depending upon the context(18).”
Chen, J.-X., Zeng, H., Reese, J., Aschner, J. L., & Meyrick, B. O. (2011) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00866.2011 · Cited by 63
“However, in the absence of VEGF, Ang-2 increases endothelial apoptosis and results in vessel regression (20).”
BackgroundWada, T., Jesmin, S., Gando, S., et al. (2013) · Journal of Inflammation · doi:10.1186/1476-9255-10-6 · Cited by 63
“However, Ang2 promotes cell survival in the presence of VEGF [12].”
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Hou, H., Chou, W., Lin, L., Tang, J., Tseng, M., Huang, C., Yao, M., Chen, C., Tsay, W., & Tien, H. (2007) · Leukemia Research · doi:10.1016/j.leukres.2007.08.010 · Cited by 63
Briasoulis, Α., Tousoulis, D., Antoniades, C. A., Παπαγεωργίου, Ν., & Stefanadis, C. (2010) · Cardiovascular Therapeutics · doi:10.1111/j.1755-5922.2009.00131.x · Cited by 63
“, green fluorescent protein (GFP)) only in cells expressing an endothelial specific gene, such as Tie-2 [128].”
BackgroundInfluentialInfluences of brain tumor-associated pH changes and hypoxia on epileptogenesis
Schaller, B. J. (2005) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.2004.00355.x · Cited by 62
Michalska-Jakubus, M. M., Kowal‐Bielecka, O., Chodorowska, G., Bielecki, M., & Krasowska, D. (2010) · Rheumatology · doi:10.1093/rheumatology/keq392 · Cited by 62
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“Moreover, Ang-2 has been shown to have a VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo (Lobov et al., 2002; Maisonpierre et al., 1997).”
BackgroundLiu, L., Cao, J., Zhao, J., Li, X., Suo, Z., & Li, H. (2019) · OncoTargets and Therapy · doi:10.2147/ott.s226851 · Cited by 61
“When ANG2 acting together with VEGFA, they can interrupt the interaction between endothelial cells, promoting vascular germination and destabilize blood vessels, activate matrix degrading enzymes, including plasminogen activator (PAS) and matrix metalloproteinase (MMPs), allowing endothelial cells to migrate and germi…”
BackgroundJaumdally, R. J., Goon, P. K. Y., Varma, C., Blann, A. D., & Lip, G. Y. H. (2009) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2009.02151.x · Cited by 62
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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