Effects of a synthetic PEG-ylated Tie-2 agonist peptide on endotoxemic lung injury and mortality
Open accessAbstract
A synthetic 7-mer, HHHRHSF, was recently identified by screening a phage display library for binding to the Tie-2 receptor. A polyethylene-oxide clustered version of this peptide, termed vasculotide (VT), was reported to activate Tie-2 and promote angiogenesis in a mouse model of diabetic ulcer. We hypothesized that VT administration would defend endothelial barrier function against sepsis-associated mediators of permeability, prevent lung vascular leakage arising in endotoxemia, and improve mortality in endotoxemic mice. In confluent human microvascular endothelial cells, VT prevented endotoxin-induced (lipopolysaccharides, LPS O111:B4) gap formation, loss of monolayer resistance, and translocation of labeled albumin. In 8-wk-old male C57Bl6/J mice given a ∼70% lethal dose of endotoxin (15 mg/kg ip), VT prevented lung vascular leakage and reversed the attenuation of lung vascular endothelial cadherin induced by endotoxemia. These protective effects of VT were associated with activation of Tie-2 and its downstream mediator, Akt. Echocardiographic studies showed only a nonsignificant trend toward improved myocardial performance associated with VT. Finally, we evaluated survival in this mouse model. Pretreatment with VT improved survival by 41.4% ( n = 15/group, P = 0.02) and post-LPS administration of VT improved survival by 33.3% ( n = 15/group, P = 0.051). VT-mediated protection from LPS lethality was lost in Tie-2 heterozygous mice, in agreement with VT's proposed receptor specificity. We conclude that this synthetic Tie-2 agonist, completely unrelated to endogenous Tie-2 ligands, is sufficient to activate the receptor and its downstream pathways in vivo and that the Tie-2 receptor may be an important target for therapeutic evaluation in conditions of pathological vascular leakage.
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Cites
The Acute Respiratory Distress Syndrome
Matthay, M. A. (1996) · New England Journal of Medicine · doi:10.1056/nejm199605303342209 · Cited by 4,924 · see citing works
The Acute Respiratory Distress Syndrome
Ware, L. B., & Matthay, M. A. (2000) · New England Journal of Medicine · doi:10.1056/nejm200005043421806 · Cited by 4,666 · see citing works
Requisite Role of Angiopoietin-1, a Ligand for the TIE2 Receptor, during Embryonic Angiogenesis
Suri, C., Jones, P. F., Patan, S., Bartunkova, S., Maisonpierre, P. C., Davis, S. H., Sato, T. N., & Yancopoulos, G. D. (1996) · Cell · doi:10.1016/s0092-8674(00)81813-9 · Cited by 2,831 · see citing works
Leakage-Resistant Blood Vessels in Mice Transgenically Overexpressing Angiopoietin-1
Thurston, G., Suri, C., Smith, K., McClain, J., Sato, T. T., Yancopoulos, G. D., & McDonald, D. M. (1999) · Science · doi:10.1126/science.286.5449.2511 · Cited by 1,350 · see citing works
Angiopoietin-1 protects the adult vasculature against plasma leakage
Thurston, G., Rudge, J. S., Ioffe, E., Zhou, H., Ross, L. H., Croll, S. D., Glazer, N. L., Holash, J. A., McDonald, D. M., & Yancopoulos, G. D. (2000) · Nature Medicine · doi:10.1038/74725 · Cited by 1,284 · see citing works
Russell, J. A. (2006) · New England Journal of Medicine · doi:10.1056/nejmra043632 · Cited by 1,042 · see citing works
Dumont, D. J., Gradwohl, G., Fong, G. H., Puri, M. C., Gertsenstein, M., Auerbach, A., & Breitman, M. L. (1994) · Genes & Development · doi:10.1101/gad.8.16.1897 · Cited by 985 · see citing works
Self-citationCytoskeletal regulation of pulmonary vascular permeability
Dudek, S. M., & Garcia, J. G. N. (2001) · Journal of Applied Physiology · doi:10.1152/jappl.2001.91.4.1487 · Cited by 985 · see citing works
Garcia, J. G. N., Liu, F., Verin, A. D., Birukova, A. A., Dechert, M. A., Gerthoffer, W. T., Bamberg, J. R., & English, D. K. (2001) · Journal of Clinical Investigation · doi:10.1172/jci12450 · Cited by 886 · see citing works
Dejana, E., Tournier‐Lasserve, E., & Weinstein, B. M. (2009) · Developmental Cell · doi:10.1016/j.devcel.2009.01.004 · Cited by 787 · see citing works
A morphological biosensor for mammalian cells
Giæver, I., & Keese, C. R. (1993) · Nature · doi:10.1038/366591a0 · Cited by 775 · see citing works
Mei, S. H. J., McCarter, S. D., Deng, Y., Parker, C. H., Liles, W. C., & Stewart, D. J. (2007) · PLoS Medicine · doi:10.1371/journal.pmed.0040269 · Cited by 618 · see citing works
Excess Circulating Angiopoietin-2 May Contribute to Pulmonary Vascular Leak in Sepsis in Humans
Parikh, S. M., Mammoto, T., Schultz, A., Yuan, H.-T., Christiani, D., Karumanchi, S. A., & Sukhatme, V. P. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030046 · Cited by 527 · see citing works
Self-citationVenneri, M. A., Palma, M. D., Ponzoni, M., Pucci, F., Scielzo, C., Zonari, E., Mazzieri, R., Doglioni, C., & Naldini, L. (2007) · Blood · doi:10.1182/blood-2006-10-053504 · Cited by 504 · see citing works
Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2
Oliner, J. D., Min, H., Leal, J., Yu, D., Rao, S., You, E., Xiu, T., Kim, H. J., MEYER, S. R., Han, S. J., et al. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.09.030 · Cited by 471 · see citing works
Tiruppathì, C., Malik, A. B., Vecchio, P. J. D., Keese, C. R., & Giæver, I. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.17.7919 · Cited by 434 · see citing works
Angiopoietin 2 Is a Partial Agonist/Antagonist of Tie2 Signaling in the Endothelium
Yuan, H. T., Khankin, E. V., Karumanchi, S. A., & Parikh, S. M. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.01472-08 · Cited by 374 · see citing works
Self-citationHyperoxia causes angiopoietin 2–mediated acute lung injury and necrotic cell death
Bhandari, V., Choo-Wing, R., Lee, C. G., Zhu, Z., Nedrelow, J. H., Chupp, G. L., Zhang, X., Matthay, M. A., Ware, L. B., Homer, R., et al. (2006) · Nature Medicine · doi:10.1038/nm1494 · Cited by 337 · see citing works
Pucci, F., Venneri, M. A., Biziato, D., Nonis, A., Moi, D., Sica, A., Serio, C. D., Naldini, L., & Palma, M. D. (2009) · Blood · doi:10.1182/blood-2009-01-200931 · Cited by 328 · see citing works
The association of endothelial cell signaling, severity of illness, and organ dysfunction in sepsis
Shapiro, N. I., Schüetz, P., Yano, K., Sorasaki, M., Parikh, S. M., Jones, A. E., Trzeciak, S., Ngo, L. H., & Aird, W. C. (2010) · Critical Care · doi:10.1186/cc9290 · Cited by 268 · see citing works
Self-citationFang, X., Neyrinck, A. P., Matthay, M. A., & Lee, J. W. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.119917 · Cited by 258 · see citing works
Angiopoietin-2 is increased in severe sepsis: Correlation with inflammatory mediators
Orfanos, S. E., Kotanidou, A. N., Glynos, C., Athanasiou, C., Tsigkos, S., Dimopoulou, I., Sotiropoulou, C., Zakynthinos, S. G., Armaganidis, A., Papapetropoulos, A., et al. (2006) · Critical Care Medicine · doi:10.1097/01.ccm.0000251640.77679.d7 · Cited by 211 · see citing works
Protective Role of Angiopoietin-1 in Endotoxic Shock
Witzenbichler, B., Westermann, D., Knueppel, S., Schultheiss, H., & Tschöpe, C. (2004) · Circulation · doi:10.1161/01.cir.0000151287.08202.8e · Cited by 199 · see citing works
Angiopoietin-1 Promotes Cardiac and Skeletal Myocyte Survival Through Integrins
Dallabrida, S. M., Ismail, N. S., Oberle, J., Himes, B. E., & Rupnick, M. A. (2005) · Circulation Research · doi:10.1161/01.res.0000158285.57191.60 · Cited by 192 · see citing works
Angiopoietin-1 Requires p190 RhoGAP to Protect against Vascular Leakage in Vivo
Mammoto, T., Parikh, S. M., Mammoto, A., Gallagher, D. C., Chan, B., Mostoslavsky, G., Ingber, D. E., & Sukhatme, V. P. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702169200 · Cited by 180 · see citing works
Self-citationOligomerization and Multimerization Are Critical for Angiopoietin-1 to Bind and Phosphorylate Tie2
Kim, K.-T., Choi, H.-H., Steinmetz, M. O., Maco, B., Kammerer, R. A., Ahn, S. Y., Kim, H.-Z., Lee, G. M., & Koh, G. Y. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m500292200 · Cited by 170 · see citing works
Kümpers, P., Lukasz, A. H., David, S., Horn, R., Hafer, C., Faulhaber‐Walter, R., Fliser, D., Haller, H. G., & Kielstein, J. T. (2008) · Critical Care · doi:10.1186/cc7130 · Cited by 162 · see citing works
Self-citationProcopio, W. N., Pelavin, P. I., Lee, W. M. F., & Yeilding, N. M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.42.30196 · Cited by 156 · see citing works
Gallagher, D. C., Parikh, S. M., Balonov, K., Miller, A. C., Gautam, S., Talmor, D. S., & Sukhatme, V. P. (2008) · Shock · doi:10.1097/shk.0b013e31815dd92f · Cited by 133 · see citing works
Self-citationTournaire, R., Simon, M., le Noble, F., et al. (2004) · EMBO Reports · doi:10.1038/sj.embor.7400100 · Cited by 88 · see citing works
Wu, L., Zaborina, O. Y., Zaborin, A., Chang, E. B., Musch, M. W., Holbrook, C., Shapiro, J. A., Turner, J. R., Wu, G., Lee, K. Y. C., et al. (2004) · Gastroenterology · doi:10.1053/j.gastro.2003.11.011 · Cited by 80 · see citing works
Renoprotective effect of COMP-angiopoietin-1 in db/db mice with type 2 diabetes
Lee, S., Kim, W., Moon, S.-O., Sung, M. J., Kim, D. H., Kang, K. P., Jang, K. Y., Lee, S., Park, B. H., Koh, G. Y., et al. (2006) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfl598 · Cited by 77 · see citing works
Antibody-mediated pure red cell aplasia (PRCA): epidemiology, immunogenicity and risks
Macdougall, I. C. (2005) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfh1087 · Cited by 77 · see citing works
Angiopoietin-2-Driven Vascular Remodeling in Airway Inflammation
Tabruyn, S. P., Colton, K., Morisada, T., Fuxe, J., Wiegand, S. J., Thurston, G., Coyle, A. J., Connor, J. R., & McDonald, D. M. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.100059 · Cited by 62 · see citing works
Acceleration of Diabetic Wound Healing by an Angiopoietin Peptide Mimetic
Slyke, P. V., Alami, J., Martin, D., Kuliszewski, M. A., Leong-Poi, H. M., Sefton, M. V., & Dumont, D. J. (2008) · Tissue Engineering Part A · doi:10.1089/ten.tea.2007.0400 · Cited by 60 · see citing works
Self-citationKugathasan, L., Ray, J. B., Deng, Y., Rezaei, E., Dumont, D., & Stewart, D. J. (2009) · The Journal of Experimental Medicine · doi:10.1084/jem.20090389 · Cited by 59 · see citing works
Self-citationChiang, E. T., Camp, S. M., Dudek, S. M., et al. (2008) · Microvascular Research · doi:10.1016/j.mvr.2008.11.007 · Cited by 53 · see citing works
Angiopoietin-1 Protects against Airway Inflammation and Hyperreactivity in Asthma
Simoes, D. C. M., Vassilakopoulos, T., Toumpanakis, D., Petrochilou, K., Roussos, C., & Papapetropoulos, A. (2008) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200708-1141oc · Cited by 43 · see citing works
Angiopoietin-1 variant, COMP-Ang1 attenuates hydrogen peroxide-induced acute lung injury
Kim, S. R., Lee, K. S., Park, S. J., Min, K. H., Lee, K. Y., Choe, Y. H., Hong, S. H., Koh, G. Y., & Lee, Y. C. (2008) · Experimental & Molecular Medicine · doi:10.3858/emm.2008.40.3.320 · Cited by 38 · see citing works
Angiopoietin-1 Induces Migration of Monocytes in a Tie-2 and Integrin-Independent Manner
Ahmad, S., Cudmore, M., Wang, K., Hewett, P. W., Potluri, R., Fujisawa, T., & Ahmed, A. (2010) · Hypertension · doi:10.1161/hypertensionaha.110.155556 · Cited by 25 · see citing works
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Endothelial destabilization by angiopoietin-2 via integrin β1 activation
Hakanpaa, L., Sipila, T., Leppanen, V.-M., Gautam, P., Nurmi, H., Jacquemet, G., Eklund, L., Ivaska, J., Alitalo, K., & Saharinen, P. (2015) · Nature Communications · doi:10.1038/ncomms6962 · Cited by 287 · see citing works
Clajus, C., Lukasz, A., David, S., Hertel, B., Lichtinghagen, R., Parikh, S. M., Simon, A., Ismail, I., Haller, H., & Kümpers, P. (2012) · Cytokine · doi:10.1016/j.cyto.2012.04.002 · Cited by 44 · see citing works
Self-citation
- Authors
- David, S., Ghosh, C. C., Kümpers, P., Shushakova, N., Van Slyke, P., Khankin, E. V., Karumanchi, S. A., Dumont, D., & Parikh, S. M.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- University Hospital Münster (DE)
- Medizinische Hochschule Hannover (DE)
- Molecular and Cellular Biology Research, Sunnybrook Research Institute, and Department of Medical Biophysics, University of Toronto, Ontario, Canada; and
- University of Toronto (CA)
- Corresponding author
- Parikh, Samir M.
- ORCID
- Venue
- American Journal of Physiology-Lung Cellular and Molecular Physiology
- Publisher
- American Physiological Society
- Published
- 2011-06
- Volume
- 300
- Issue
- 6
- Pages
- L851-L862
- ISSN
- 1040-0605 (ISSN-L)
- 1522-1504
- PMC
- PMC3119126
- OpenAlex
- W2169581734
- Cited by
- 96
- References
- 40
- Citations by year
- 2026: 2 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 9 · 2020: 6 · 2019: 7 · 2018: 10 · 2017: 8 · 2016: 6 · 2015: 13 · 2014: 8 · 2013: 8 · 2012: 10
- FWCI
- 6.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Lung Cellular and Molecular Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL093234)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK06916)
- Topics
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Respiratory Support and Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- Tie2 receptor, PEGylated peptide, endotoxemia, lipopolysaccharide, sepsis, lung injury, vascular leakage, endothelial barrier function, Akt signaling, survival, angiogenesis, phage display peptides
- MeSH terms
- Animals, Capillary Permeability, Endothelium, Vascular, Endotoxins, Humans, Immunoenzyme Techniques, Lipopolysaccharides, Male, Mice, Inbred C57BL, Peptide Fragments, Polyethylene Glycols, RNA, Messenger, Blotting, Western, Survival Rate, Endotoxemia, Reverse Transcriptase Polymerase Chain Reaction, Receptor, TIE-2, Mice, Lung Injury
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