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Angiopoietin-1 protects the adult vasculature against plasma leakage

Nature Medicine volume 6, pages 460–463 (2000)Cite this article

Abstract

Pathological increases in vascular leakage lead to edema and swelling, causing serious problems in brain tumors, in diabetic retinopathy, after strokes, during sepsis and also in inflammatory conditions such as rheumatoid arthritis and asthma. Although many agents and disease processes increase vascular leakage, no known agent specifically makes vessels resistant to leaking. Vascular endothelial growth factor1 (VEGF) and the angiopoietins2 function together during vascular development, with VEGF acting early during vessel formation3,4,5, and angiopoietin-1 acting later during vessel remodeling, maturation and stabilization6,7,8,9. Although VEGF was initially called vascular permeability factor10,11, there has been less focus on its permeability actions and more effort devoted to its involvement in vessel growth and applications in ischemia and cancer. Recent transgenic approaches have confirmed the profound permeability effects of VEGF (refs. 12–14), and have shown that transgenic angiopoietin-1 acts reciprocally as an anti-permeability factor when provided chronically during vessel formation14, although it also profoundly affects vascular morphology when thus delivered14,15. To be useful clinically, angiopoietin-1 would have to inhibit leakage when acutely administered to adult vessels, and this action would have to be uncoupled from its profound angiogenic capabilities. Here we show that acute administration of angiopoietin-1 does indeed protect adult vasculature from leaking, countering the potentially lethal actions of VEGF and inflammatory agents.

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Figure 1: Adenoviral infection by Ad–VEGF and Ad–Ang1 leads to specific expression of adenovirally produced products in the liver, producing circulating VEGF or angiopoietin-1, and resulting in dose-dependent reduction in survival after administration of Ad–VEGF but not Ad–Ang1.
Figure 2: Administration of Ad–VEGF leads to systemic vascular leakage in C57BL/6 mice.
Figure 3: Systemic angiopoietin-1 production by adenoviral gene delivery causes resistance to vascular leakage induced by mustard oil and VEGF.
Figure 4: Vessel morphology in lectin-stained whole mounts of ear skin.

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References

  1. Ferrara, N. Vascular endothelial growth factor: molecular and biological aspects. Curr. Top. Microbiol. Immunol. 237, 1– 30 (1999).

    CAS  PubMed  Google Scholar 

  2. Davis, S. & Yancopoulos, G.D. The angiopoietins: Yin and Yang in angiogenesis. Curr. Top. Microbiol. Immunol. 237, 173–185 (1999).

    CAS  PubMed  Google Scholar 

  3. Shalaby, F. et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62–66 (1995).

    Article  CAS  Google Scholar 

  4. Carmeliet, P. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435–439 (1996).

    Article  CAS  Google Scholar 

  5. Ferrara, N. et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439– 442 (1996).

    Article  CAS  Google Scholar 

  6. Dumont, D.J. et al. Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev. 8, 1897– 1909 (1994).

    Article  CAS  Google Scholar 

  7. Sato, T.N. et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376, 70 –74 (1995).

    Article  CAS  Google Scholar 

  8. Davis, S. et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87, 1161–1169 (1996).

    Article  CAS  Google Scholar 

  9. Suri, C. et al. Requisite role of Angiopoietin-1, a ligand for the Tie2 receptor, during embryonic angiogenesis. Cell 87, 1171–1180 (1996).

    Article  CAS  Google Scholar 

  10. Senger, D.R. et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219, 983–985 (1983).

    Article  CAS  Google Scholar 

  11. Dvorak, H.F., Nagy, J.A., Feng, D., Brown, L.F. & Dvorak, A.M. Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis . Curr. Top. Microbiol. Immunol. 237, 97 –132 (1999).

    CAS  PubMed  Google Scholar 

  12. Detmar, M. et al. Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice. J. Invest. Dermatol. 111, 1–6 (1998 ).

    Article  CAS  Google Scholar 

  13. Larcher, F., Murillas, R., Bolontrade, M., Conti, C.J. & Jorcano, J.L. VEGF/VPF overexpression in skin of transgenic mice induces angiogenesis, vascular hyperpermeability and accelerated tumor development. Oncogene 17, 303– 311 (1998).

    Article  CAS  Google Scholar 

  14. Thurston, G. et al. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286, 2511– 2514 (1999).

    Article  CAS  Google Scholar 

  15. Suri, C. et al. Angiopoietin-1 promotes increased vascularization in vivo . Science 282, 468– 471 (1998).

    Article  CAS  Google Scholar 

  16. Massie, B., Gluzman, Y. & Hassell, J.A. Construction of a helper-free recombinant adenovirus that expresses polyomavirus large T antigen. Mol. Cell Biol. 6, 2872–2883 (1986).

    Article  CAS  Google Scholar 

  17. Berkner, K.L. Development of adenovirus vectors for the expression of heterologous genes . Biotechniques 6, 616– 629 (1988).

    CAS  PubMed  Google Scholar 

  18. Herz, J. & Gerard, R.D. Adenovirus-mediated transfer of low density lipoprotein receptor gene acutely accelerates cholesterol clearance in normal mice. Proc. Natl. Acad. Sci. USA 90, 2812–2816 (1993).

    Article  CAS  Google Scholar 

  19. Willnow, T.E., Sheng, Z., Ishibashi, S. & Herz, J. Inhibition of hepatic chylomicron remnant uptake by gene transfer of a receptor antagonist. Science 264, 1471–1474 ( 1994).

    Article  CAS  Google Scholar 

  20. Muzzin, P., Eisensmith, R.C., Copeland, K.C. & Woo, S.L. Correction of obesity and diabetes in genetically obese mice by leptin gene therapy. Proc. Natl. Acad. Sci. USA 93, 14804–14808 (1996).

    Article  CAS  Google Scholar 

  21. Jancso, G., Pierau, F.K. & Sann, H. Mustard oil-induced cutaneous inflammation in the pig . Agents Actions 39, 31– 34 (1993).

    Article  CAS  Google Scholar 

  22. Lippe, I.T., Stabentheiner, A. & Holzer, P. Participation of nitric oxide in the mustard oil-induced neurogenic inflammation of the rat paw skin. Eur. J. Pharmacol. 232, 113–120 ( 1993).

    Article  CAS  Google Scholar 

  23. Collins, P.D., Connolly, D.T. & Williams, T.J. Characterization of the increase in vascular permeability induced by vascular permeability factor in vivo. Br. J. Pharmacol. 109, 195–199 ( 1993).

    Article  CAS  Google Scholar 

  24. Hehir, K.M. et al. Molecular characterization of replication-competent variants of adenovirus vectors and genome modifications to prevent their occurrence . J. Virol. 70, 8459–8467 (1996)

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Thurston, G., Baluk, P., Hirata, A. & McDonald, D.M. Permeability-related changes revealed at endothelial cell borders in inflamed venules by lectin binding. Am. J. Physiol. 271, H2547– 2562 (1996).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank C. Suri, N. Gale and R. Torres, as well as the entire Regeneron community, for scientific discussion; K. Smith for technical assistance at the University of California at San Francisco; S. Mahon for technical assistance at Regeneron; D. Hylton for enzyme-linked immunosorbent assays; and E. Burrows for graphics production. This work was supported by National Institutes of Health grants HL59157 & HL24136 (National Heart, Lung and Blood Institute).

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Authors and Affiliations

  1. Department of Anatomy & Cardiovascular Research Institute, University of California, San Francisco, 94143, California, USA

    Gavin Thurston, Nicole Glazer & Donald M. McDonald

  2. Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, 10591, NY, USA

    John S. Rudge, Ella Ioffe, Hao Zhou, Leorah Ross, Susan D. Croll, Jocelyn Holash & George D. Yancopoulos

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  1. Gavin Thurston
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Correspondence to Gavin Thurston or George D. Yancopoulos.

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Thurston, G., Rudge, J., Ioffe, E. et al. Angiopoietin-1 protects the adult vasculature against plasma leakage . Nat Med 6, 460–463 (2000). https://doi.org/10.1038/74725

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