Abstract
The cellular expression of Angiopoietin-2 (Ang2) was studied during lymphatic development in mouse by immunohistochemistry and compared to that of lymphatic endothelial markers. At the earliest stage of lymphvasculogenesis, Prox1-identified lymphatic precursor cells of the cardinal vein displayed an intense immunoreaction for Ang2 in their cytoplasm, implying that Ang2 may adjust lymphatic specification and sprouting from the veins under the control of Prox1. Thereafter, Ang2 was constantly expressed in Prox1 and/or LYVE-1-immunopositive endothelial cells of lymphatic sacs and vessels, ranging from lymphatic capillaries to collectors, throughout embryonic and neonatal development, and the lymphatic endothelial cells simultaneously exhibited immunoreactivity to Tie2, a primary receptor for angiopoietins. These results suggest that lymphatic endothelial cells may regulate lymphatic development via their own Ang2-Tie2 signaling. Ang2 is further immunolocalized in the developing blood vessels including hepatic sinusoids, adrenal medullary vasculature and postnatal pulmonary vessels, thereby indicating that the blood vessels, which undergo vascular remodeling and sudden alteration of blood flow during the development, are also likely to express Ang2. The present study is first to demonstrate Ang2 expression in the lymphatic endothelial cells during development, and consequently Ang2 is regarded as a molecular profile of the developing lymphatic endothelial cells required for lymphatic vascular organization.
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References
Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8:464–478
Banerji S, Ni J, Wang SX, Clasper S, Su J, Tammi R, Jones M, Jackson DG (1999) LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 144:789–801
Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radjewski C, Maisonpierre PC, Yancopoulos GD (1996) Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87:1161–1169
Eklund L, Olsen BR (2006) Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling. Exp Cell Res 312:630–641
Gale NW, Thurston G, Hackett SF, Renard R, Wang Q, McClain J, Martin C, Witte C, Witte MH, Jackson D, Suri C, Campochiaro PA, Wiegand SJ, Yancopoulos GD (2002) Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev Cell 3:411–423
Hackett SF, Wiegand S, Yancopoulos GD, Campochiaro PA (2002) Angiopoietin-2 plays an important role in retinal angiogenesis. J Cell Physiol 192:182–187
Hazzard TM, Christenson LK, Stouffer RL (2000) Changes in expression of vascular endothelial growth factor and angiopoietin-1 and -2 in the macaque corpus luteum during the menstrual cycle. Mol Hum Reprod 6:993–998
Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284:1994–1998
Jones N, Iljin K, Dumont DJ, Alitalo K (2001) Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat Rev Mol Cell Biol 2:257–267
Leach L, Babawale MO, Anderson M, Lammiman M (2002) Vasculogenesis, angiogenesis and the molecular organization of endothelial junctions in the early human placenta. J Vasc Res 39:246–259
Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60
Mäkinen T, Norrmén C, Petrova T (2007) Molecular mechanisms of lymphatic vascular development. Cell Mol Life Sci 64:1915–1929
Nguyen VPKH, Hen SH, Trinh J, Kim H, Coomber BL, Dumont DJ (2007) Differential response of lymphatic, venous and arterial endothelial cells to angiopoietin-1 and angiopoietin-2. BMC Cell Biol 8:10–25
Oliver G, Sosa-Pineda B, Geisendorf S, Sapana EP, Doe CQ, Grus P (1993) Prox1, a prospero-related homeobox gene expressed during mouse development. Mech Dev 4:3–16
Prevo R, Banerji S, Ferguson DJ, Clasper S, Jackson DG (2001) Mouse LYVE-1 is an endocytic receptor for hyaluronan in lymphatic endothelium. J Biol Chem 276:19420–19430
Sato A, Iwama A, Takakura N, Nishio H, Yancopoulos GD, Suda T (1998) Characterization of TEK receptor tyrosine kinase and its ligands, Angiopoietins, in human hematopoietic progenitor cells. Int Immunol 10:1217–1227
Shimoda H, Bernas MJ, Witte MH, Gale NW, Yancopoulos GD, Kato S (2007) Abnormal recruitment of periendothelial cells to lymphatic capillaries in digestive organs of angiopoietin-2-deficient mice. Cell Tissue Res 328:329–337
Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD (1996) Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87:1171–1180
Thurston G (2003) Role of angiopoietins and Tie receptor tyrosine kinases in angiogenesis and lymphangiogenesis. Cell Tissue Res 314:61–68
Visconti R, Richardson CD, Sato TN (2002) Orchestration of angiogenesis and arteriovenous contribution by angiopoietins and vascular endothelial growth factor (VEGF). Proc Natl Acad Sci USA 99:8219–8224
Ward NL, Dumont DJ (2002) The angiopoietins and Tie2/Tek: adding to the complexity of cardiovascular development. Semin Cell Dev Biol 13:19–27
Wigle JT, Harvey N, Detmar M, Lagutina I, Grosveld G, Gunn MD, Jackson DG, Oliver G (2002) An essential role of Prox1 in the induction of the lymphatic endothelial phenotype. EMBO J 21:1505–1513
Wulff C, Wilson H, Largue P, Duncan WC, Armstrong DG, Fraser HM (2000) Angiogenesis in the human corpus luteum: localization and changes in angiopoietins, Tie-2, and vascular endothelial growth factor messenger ribonucleic acid. J Clin Endocrinol Metab 85:4302–4309
Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J (2000) Vascular-specific growth factors and blood vessel formation. Nature 407:242–248
Yuan HT, Suri C, Landon DN, Yancopoulos GD, Woolf AS (2000) Angiopoietin-2 is a site-specific factor in differentiation of mouse renal vasculature. J Am Soc Nephrol 11:1055–1066
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The author is grateful to Mr. Tooru Kajiwara for his expert technical assistance.
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Shimoda, H. Immunohistochemical demonstration of Angiopoietin-2 in lymphatic vascular development. Histochem Cell Biol 131, 231–238 (2009). https://doi.org/10.1007/s00418-008-0513-9
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DOI: https://doi.org/10.1007/s00418-008-0513-9