Cited by 676Angiogenesis and VEGF in CancerLymphatic System and DiseasesBarrier Structure and Function Studies

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Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo

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Lobov, Ivan B., Brooks, Peter C., Lang, Richard A.·2002·Proceedings of the National Academy of Sciences

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Abstract

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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Background
Expression of Angiopoietin-2 is Correlated with Vascularization and Tumor Size in Human Colorectal Adenocarcinoma
Wang, H.-L., Deng, C.-S., Lin, J., Pan, D.-Y., Zou, Z.-Y., & Zhou, X.-Y. (2007) · The Tohoku Journal of Experimental Medicine · doi:10.1620/tjem.213.33 · Cited by 23
“This might be a reason for causing lymph-node metastases, revealing the critical role of Ang-2 in the process of tumor metastatic spread (Lobov et al. 2002; Yoshiji et al. 2005).”
Background
Angiogenic activity of endothelial progenitor cells through angiopoietin-1 and angiopoietin-2
Siavashi, V., Sariri, R., Nassiri, S. M., Esmaeilivand, M., Asadian, S., Cheraghi, H., Barekati‐Mowahed, M., & Rahbarghazi‬, R. (2016) · Animal Cells and Systems · doi:10.1080/19768354.2016.1189961 · Cited by 23
“In the literature it was demonstrated that sustained increase of Ang-2, coupled with reciprocal decrease in Ang-1 content contributed to proliferation and migration of ECs in angiogenic milieu (Lobov et al. 2002).”
Background
The angiogenic potential of CD271+ human adipose tissue-derived mesenchymal stem cells
Smith, R. J. P., Faroni, A., Barrow, J. R., et al. (2021) · Stem Cell Research & Therapy · doi:10.1186/s13287-021-02177-0 · Cited by 23
“In low-VEGF environments, ANGPT2 inhibits the Tie2 receptor and promotes cell death, while in high-VEGF environments, ANGPT2 activates the Tie2 receptor in a unique pathway that produces vascular plasticity and prompts capillary growth [31].”
Background
Angiopoietin-2 Deficiency Decelerates Age-Dependent Vascular Changes in the Mouse Retina
Feng, Y., Pfister, F., Schreiter, K., Wang, Y., Stock, O., Hagen, F. V., Wolburg, H., Hoffmann, S., Deutsch, U., & Hammes, H. (2008) · Cellular Physiology and Biochemistry · doi:10.1159/000113755 · Cited by 23
Lysophosphatidic acid contributes to angiogenic homeostasis
Kazlauskas, A. (2014) · Experimental Cell Research · doi:10.1016/j.yexcr.2014.11.012 · Cited by 23
Angiopoietin-4 increases permeability of blood vessels and promotes lymphatic dilation
Kesler, C. T., Pereira, E. R., Cui, C. H., Nelson, G. M., Masuck, D. J., Baish, J. W., & Padera, T. P. (2015) · The FASEB Journal · doi:10.1096/fj.14-268920 · Cited by 23
Systemic soluble Tie2 expression inhibits and regresses corneal neovascularization
Singh, N., Macnamara, E., Rashid, S., Ambati, J., Kontos, C. D., Higgins, E., & Ambati, B. K. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.04.108 · Cited by 23
Alteration of the vascular endothelial growth factor and angiopoietins-1 and -2 pathways in transitional cell carcinomas of the urinary bladder associated with tumor progression.
Quentin, T., Schlott, T., Korabiowska, M., et al. (2004) · PubMed · Cited by 23
Relationship Between Vascular Endothelial Growth Factor and Angiopoietin-2 in Asthmatics Before and After Inhaled Beclomethasone Therapy
Nomura, S., Kanazawa, H., Hirata, K., et al. (2005) · Journal of Asthma · doi:10.1081/jas-51346 · Cited by 23
“In contrast, in the presence of low levels of VEGF, Ang-2 leads to vessel regression (18, 19).”
Background
Immunohistochemical expression of von Willebrand factor in the preeclamptic placenta
Parra-Cordero, M., Bosco, C., González, J., Gutiérrez, R., Barja, P., & Rodrigo, R. (2011) · Journal of Molecular Histology · doi:10.1007/s10735-011-9351-5 · Cited by 22
“Many studies have reported that oxidative stress could be the cause of endothelial failure (Lobov et al. 2002), but recent trials have reported that endothelial dysfunction in preeclampsia may be caused by immune dysfunction (Geva et al. 2002).”
Background
Effects of Angiopoietin-2 on Transplanted Mouse Ovarian Tissue
Youm, H. W., Lee, J. W., Kim, E. J., Kong, H. S., Lee, J. R., Suh, C. S., & Kim, S. H. (2016) · PLoS ONE · doi:10.1371/journal.pone.0166782 · Cited by 22
Prolonged Mechanical Ventilation Alters the Expression Pattern of Angio-neogenetic Factors in a Pre-Clinical Rat Model
Bruells, C. S., Maes, K., Rossaint, R., Thomas, D., Cielen, N., Bleilevens, C., Bergs, I., Loetscher, U., Dreier, A., Gayan‐Ramirez, G., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0070524 · Cited by 22
Stimulation of functional vessel growth by gene therapy.
Korpisalo, P., & Ylä-Herttuala, S. (2010) · Integrative Biology · doi:10.1039/b921869f · Cited by 23
Angiopoietin-2 overexpression in morris hepatoma results in increased tumor perfusion and induction of critical angiogenesis-promoting genes.
Kunz, P., Hoffend, J., Altmann, A., Dimitrakopoulou‐Strauss, A., Koczan, D., Eisenhut, M., Bonaterra, G. A., Dengler, T. J., Mier, W., Haberkorn, U., et al. (2006) · PubMed · Cited by 21
Tumor vasculature: the Achilles' heel of cancer?
Johannessen, T.-C. A., Wagner, M., Straume, O., Bjerkvig, R., & Eikesdal, H. P. (2012) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2013.730522 · Cited by 21
Serum Levels of Angiopoietin-2, but not Angiopoietin-1, are Elevated in Patients with Erythrodermic Cutaneous T-cell Lymphoma
Kawaguchi, M., Sugaya, M., Suga, H., et al. (2014) · Acta Dermato Venereologica · doi:10.2340/00015555-1633 · Cited by 21
Endothelial loss of Fzd5 stimulates PKC/Ets1-mediated transcription of Angpt2 and Flt1
Brandt, M. M., Dijk, C. V., Chrifi, I., et al. (2018) · Angiogenesis · doi:10.1007/s10456-018-9625-6 · Cited by 21
Fucoxanthin Exerts Anti-Tumor Activity on Canine Mammary Tumor Cells via Tumor Cell Apoptosis Induction and Angiogenesis Inhibition
Jang, H. J., Choi, J., Park, J.-K., Won, G., & Seol, J. (2021) · Animals · doi:10.3390/ani11061512 · Cited by 21
“In the absence of VEGF, Ang2 exerts the opposite effect [40].”
Background
Synergistic effect of vascular endothelial growth factor and angiopoietin-2 on progression free survival in multiple myeloma
Bhaskar, A., Gupta, R., Sreenivas, V., et al. (2013) · Leukemia Research · doi:10.1016/j.leukres.2012.12.014 · Cited by 21
Roles of vascular endothelial growth factor, Angiopoietin 1, and Angiopoietin 2 in nasal polyp
Park, S. K., Kim, H. I., & Yang, Y. I. (2009) · The Laryngoscope · doi:10.1002/lary.20085 · Cited by 21
“However, in the presence of low levels of VEGF, Ang-2 triggers vessel regression.(15) In our experiments, VEGF and Ang-1 levels were significantly higher, whereas the Ang-2 level was significantly lower in nasal polyps than in inferior turbinates.”
Background
Early Systemic Microvascular Damage in Pigs with Atherogenic Diabetes Mellitus Coincides with Renal Angiopoietin Dysbalance
Khairoun, M., van den Heuvel, M., van den Berg, B. M., Sorop, O., de Boer, R. D. H., van Ditzhuijzen, N. S., Bajema, I. M., Baelde, H. J., Zandbergen, M., Duncker, D. J., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0121555 · Cited by 21
Hepatitis B virus/hepatitis C virus upregulate angiopoietin‐2 expression through mitogen‐activated protein kinase pathway
Li, Y., Chen, J., Wu, C., et al. (2010) · Hepatology Research · doi:10.1111/j.1872-034x.2010.00712.x · Cited by 21
MRI assessment of hemodynamic effects of angiopoietin-2 overexpression in a brain tumor model
Valable, S., Eddi, D., Constans, J., Guillamo, J., Bernaudin, M., Roussel, S., & Petit, E. (2009) · Neuro-Oncology · doi:10.1215/15228517-2008-117 · Cited by 21
In utero angiopoietin-2 gene delivery remodels placental blood vessel phenotype: a murine model for studying placental angiogenesis
Geva, E., Ginzinger, D. G., Moore, D. H., Ursell, P. C., & Jaffe, R. B. (2005) · Molecular Human Reproduction · doi:10.1093/molehr/gah159 · Cited by 21
“…to phosphorylate the Tie2 receptor on some cells, while acting as a natural antagonist on others, suggesting that the pro-angiogenic action of Ang2 depends on the differentiation state of endothelial cells (Maisonpierre et al., 1997; Yancopoulos et al., 2000; Gale et al., 2002; Lobov et al., 2002).”
Influential
The Hidden Face of Venous Malformations
Redondo, P. (2008) · Archives of Dermatology · doi:10.1001/archderm.144.7.922 · Cited by 21
Neuroprotection in early stages of Alzheimer’s disease is promoted by transthyretin angiogenic properties
Gião, T., Saavedra, J., Vieira, J. R., Pinto, M. T., Arsequell, G., & Cardoso, I. (2021) · Alzheimer s Research & Therapy · doi:10.1186/s13195-021-00883-8 · Cited by 21
Altered uterine angiogenesis in rats treated with a glyphosate-based herbicide
Ingaramo, P. I., Alarcón, R., Caglieris, M. L., Varayoud, J., Muñoz‐de‐Toro, M., & Luque, E. H. (2021) · Environmental Pollution · doi:10.1016/j.envpol.2021.118729 · Cited by 21
ANGPTL4 influences the therapeutic response of patients with neovascular age-related macular degeneration by promoting choroidal neovascularization
Yu, Q., Dinabandhu, A., Cao, X., Sanchez, J. C., Jee, K. J., Rodrigues, M. W., Guo, C., Zhang, J., Vancel, J., Menon, D., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.157896 · Cited by 22
“ANGPT2 acts synergistically with VEGF to promote angiogenesis but is antiangiogenic in the absence of VEGF (21).”
Background
Vascular Repair and Regeneration as a Therapeutic Target for Pulmonary Arterial Hypertension
Farkas, L., & Kolb, M. R. J. (2013) · Respiration · doi:10.1159/000350177 · Cited by 20
A decreased ratio between serum levels of the antagonistic angiopoietins 1 and 2 indicates tumour progression of malignant melanoma
Gardizi, M., Kurschat, C. E., Riese, A., et al. (2012) · Archives of Dermatological Research · doi:10.1007/s00403-012-1228-2 · Cited by 20
“This is accomplished by priming ECs to proangiogenic factors like members of the VEGF-family of growth factors, and in higher concentrations, by destabilizing vessels [11].”
Background
A computational model of intussusceptive microvascular growth and remodeling
Szczerba, D., Kurz, H., & Székely, G. J. (2009) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2009.09.018 · Cited by 20
Dynamics of serum angiopoietin-2 levels correlate with efficacy of intravenous pulse cyclophosphamide therapy for interstitial lung disease associated with systemic sclerosis
Takahashi, T., Asano, Y., Akamata, K., Aozasa, N., Taniguchi, T., Noda, S., Masui, Y., Ichimura, Y., Toyama, T., Tamaki, Z., et al. (2012) · Modern Rheumatology · doi:10.1007/s10165-012-0755-1 · Cited by 24
Incomplete Dll4/Notch signaling inhibition promotes functional angiogenesis supporting the growth of skin papillomas
Djokovic, D., Trindade, A., Gigante, J., Pinho, M., Harris, A. L., & Duarte, A. (2015) · BMC Cancer · doi:10.1186/s12885-015-1605-2 · Cited by 20
“Antagonism of Ang-1 by Ang-2 dissociates perivascular cell coverage, and then in the absence of VEGF vessels regress, but in the presence of VEGF, endothelium becomes activated and vessels proliferate [28].”
Angiopoietin 1 and 2 gene and protein expression is differentially regulated in acute anti-Thy1.1 glomerulonephritis
Câmpean, V., Karpe, B., Haas, C. S., et al. (2008) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00320.2007 · Cited by 20
Serum Angiopoietin 2 acts as a diagnostic and prognostic biomarker in hepatocellular carcinoma
Ao, J., Chiba, T., Kanzaki, H., et al. (2021) · Journal of Cancer · doi:10.7150/jca.56436 · Cited by 19
Acute tumour response to a bispecific Ang-2-VEGF-A antibody: insights from multiparametric MRI and gene expression profiling
Baker, L. C. J., Boult, J. K. R., Thomas, M., Koehler, A., Nayak, T. K., Tessier, J. J. L., Ooi, C.-H., Birzele, F., Belousov, A., Zajac, M., et al. (2016) · British Journal of Cancer · doi:10.1038/bjc.2016.236 · Cited by 19
“In the absence of VEGF, Ang-2 expression can lead to vessel regression (Maisonpierre et al, 1997; Lobov et al, 2002).”
Background
The role of PIWI-interacting RNA in naringin pro-angiogenesis by targeting HUVECs
Pi, Y., Liang, Z., Jiang, Q., Chen, D., Su, Z., Ouyang, Y., Zhang, Z., Liu, J., Wen, S., Yang, L., et al. (2023) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2023.110344 · Cited by 19
Genetic variations in angiopoietin and pericyte pathways and clinical outcome in patients with resected colorectal liver metastases
Stremitzer, S., Zhang, W., Yang, D., Ning, Y., Stintzing, S., Sebio, A., Sunakawa, Y., Yamauchi, S., Matsusaka, S., El-Khoueiry, R. E., et al. (2015) · Cancer · doi:10.1002/cncr.29259 · Cited by 19
“Although ANGPT2 is considered to be proangiogenic, its biologic mechanisms of action under anti-VEGF– targeted therapy are still unclear, because ANGPT2 also acts as an antiangiogenic in the absence of VEGF.(32) ANGPT2 rs2442599 T>C and RALBP1 rs329007 A>G were associated with histologic response.”
Background
Longitudinal changes in maternal soluble endoglin and angiopoietin‐2 in women at risk for pre‐eclampsia
Khalil, A. A., Maíz, N., Garcia‐Mandujano, R., Elkhouli, M., & Nicolaides, K. H. (2014) · Ultrasound in Obstetrics and Gynecology · doi:10.1002/uog.13439 · Cited by 17
Antithrombotic therapy in ventricular assist device (VAD) management: From ancient beliefs to updated evidence. A narrative review
Morici, N., Varrenti, M., Brunelli, D., Perna, E., Cipriani, M., Ammirati, E., Frigerio, M., Cattaneo, M., & Oliva, F. G. (2018) · IJC Heart & Vasculature · doi:10.1016/j.ijcha.2018.06.005 · Cited by 18
A novel angiopoietin‐derived peptide displays anti‐angiogenic activity and inhibits tumour‐induced and retinal neovascularization
Palmer, G. M., Tiran, Z., Zhou, Z., Capozzi, M. E., Park, W., Coletta, C., Pyriochou, A., Kliger, Y., Levy, O., Borukhov, I., et al. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01677.x · Cited by 18
“Ang-2 can lead to robust angiogenesis in the presence of VEGF or to vessel regression when VEGF is absent or inhibited (Lobov et al., 2002).”
Background
Enalapril Alters Expression of Key Growth Factors in Experimental Diabetic Retinopathy
Kim, H. W., Kim, J. L., Lee, H. K., et al. (2009) · Current Eye Research · doi:10.3109/02713680903249913 · Cited by 18

Authors: Lobov, I. B., Brooks, P. C., & Lang, R. A.
Affiliations: Cincinnati Children's Hospital Medical Center (US)
Corresponding author: Lang, Richard A.
ORCID: Lobov, Ivan B.
Brooks, Peter C.
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
DOI: 10.1073/pnas.172161899
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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Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo

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