Angiopoietin-2 Is Required for Postnatal Angiogenesis and Lymphatic Patterning, and Only the Latter Role Is Rescued by Angiopoietin-1

Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
Developmental Cell (Impact Factor: 10.37). 10/2002; 3(3):411-23. DOI: 10.1016/S1534-5807(02)00217-4
Source: PubMed

ABSTRACT VEGF and Angiopoietin-1 requisitely collaborate during blood vessel development. While Angiopoietin-1 obligately activates its Tie2 receptor, Angiopoietin-2 can activate Tie2 on some cells, while it blocks Tie2 activation on others. Our analysis of mice lacking Angiopoietin-2 reveals that Angiopoietin-2 is dispensable for embryonic vascular development but is requisite for subsequent angiogenic remodeling. Unexpectedly, mice lacking Angiopoietin-2 also exhibit major lymphatic vessel defects. Genetic rescue with Angiopoietin-1 corrects the lymphatic, but not the angiogenesis, defects, suggesting that Angiopoietin-2 acts as a Tie2 agonist in the former setting, but as an antagonist in the latter setting. Our studies define a vascular growth factor whose primary role is in postnatal angiogenic remodeling and also demonstrate that members of the VEGF and Angiopoietin families collaborate during development of the lymphatic vasculature.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The angiopoietin (Ang) ligands are potential therapeutic targets for lymphatic related diseases, which include lymphedema and cancer. Ang-1 and Ang-2 functions are established, but those of Ang-4 are poorly understood. We used intravital fluorescence microscopy to characterize Ang-4 actions on T241 murine fibrosarcoma-associated vessels in mice. The diameters of lymphatic vessels draining Ang-4- or VEGF-C- (positive control) expressing tumors increased to 123 μm and 135 μm, respectively, and parental, mock-transduced (negative controls) and tumors expressing Ang-1 or Ang-2 remained at baseline (∼60 μm). Ang-4 decreased human dermal lymphatic endothelial cell (LEC) monolayer permeability by 27% while increasing human dermal blood endothelial cell (BEC) monolayer permeability by 200%. In vivo, Ang-4 stimulated a 4.5-fold increase in tumor-associated blood vessel permeability compared with control when measured using intravital quantitative multiphoton microscopy. Ang-4 activated receptor signaling in both LECs and BECs, evidenced by tyrosine kinase with Ig and endothelial growth factor homology domains-2 (TIE2) receptor, protein kinase B, and Erk1,2 phosphorylation detectable by immunoblotting. These data suggest that Ang-4 actions are mediated through cell-type-specific networks and that lymphatic vessel dilation occurs secondarily to increased vascular leakage. Ang-4 also promoted survival of LECs. Thus, blocking Ang-4 may prune the draining lymphatic vasculature and decrease interstitial fluid pressure (IFP) by reducing vascular permeability.-Kesler, C. T., Pereira, E. R., Cui, C. H., Nelson, G. M., Masuck, D. J., Baish, J. W., Padera, T. P. Angiopoietin-4 increases permeability of blood vessels and promotes lymphatic dilation. © FASEB.
    The FASEB Journal 05/2015; DOI:10.1096/fj.14-268920 · 5.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Angiopoietin-1 and -2 are endogenous ligands for the vascular endothelium-specific receptor tyrosine kinase Tie-2. The angiopoietin/Tie system plays a critical role in the regulation of endothelial cell survival and vascular maturation and stability. Apart from its well-established role in vascular morphogenesis, emerging data support the involvement of angiopoietins in inflammation and various malignancies. Previous studies have underlined the significance of several angiogenic factors in normal placental development. In addition, angiogenic imbalance is observed in pregnancy complications related to impaired placentation, such as preeclampsia (PE) and intrauterine growth restriction (IUGR). However, there is only limited information available on the role of the angiopoietin/Tie system in the establishment of a competent feto-maternal vascular system. In this review, we present the current knowledge regarding the role of angiopoietins in normal pregnancy and pregnancy complications.
    Experimental and therapeutic medicine 02/2015; 9(4). DOI:10.3892/etm.2015.2280 · 0.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The ability of small blood vessels to undergo rapid, reversible morphological changes is essential for the adaptive response to tissue injury or local infection. A canonical feature of this response is transient hyperpermeability. However, when leakiness is profound or persistent, adverse consequences accrue to the host, including organ dysfunction and shock. A growing body of literature identifies the Tie2 receptor, a transmembrane tyrosine kinase highly enriched in the endothelium, as an important regulator of vascular barrier function in health and in disease. The principal ligands of Tie2, Angiopoietins 1 and 2, exert opposite effects on this receptor in the context of inflammation. This review will focus on recent studies that have illuminated novel aspects of the exquisitely controlled Tie2 signaling axis while proposing unanswered questions and future directions for this field of study.
    01/2015; 3(1-2):e957508. DOI:10.4161/21688362.2014.957508