Skip to main content
NCBI home page
Journal of Cellular and Molecular Medicine logoLink to Journal of Cellular and Molecular Medicine
. 2007 May 1;9(1):113–121. doi: 10.1111/j.1582-4934.2005.tb00341.x

Preferential activity of Tie2 promoter in arteriolar endothelium

Mirela Anghelina 1, Leni Moldovan 1, N I Moldovan 1,2,3,✉
PMCID: PMC6741297  PMID: 15784169

Abstract

The tyrosine kinase Tie2/Tek (the receptor for angiopoietins) is considered one of the most reliable markers of the endothelial phenotype, across organisms, organs, and developmental stages. However, endothelium is intrinsically heterogeneous in origin, composition and function, presenting an arteriolar/venular asymmetry. In this regard, the expression of Tie2 along the vascular tree, although thought to be homogenous, has not been systematically investigated. Therefore we questioned whether the activity of Tie2 promoter is uniform in the microvascular endothelium. To this end, we analyzed in situ the expression of the markers β‐galactosidase [LacZ(Tie2)] and green fluorescent protein (GFP) [GFP(Tie2)], placed under the Tie2 promoter in transgenic mice, in whole mount tissue samples, which allow the simultaneous evaluation of its relative distribution in various microvascular compartments. In the mesenteries of LacZ(Tie2) and GFP(Tie2) mice, we found that the activity of Tie2 promoter is asymmetrically distributed, being much stronger in arteries and arterioles than on the venular side of the vascular tree. This observation was replicated in the diaphragm of LacZ(Tie2) mice. The capillaries presented a mosaic pattern of Tie2 promoter activity. Stimulation of angiogenesis either by wounding, or by intraperitoneal injection of Vascular Endothelial Growth Factor (VEGF), revealed that the arteriolar/venular asymmetry is established at endothelial cellular level early during new capillary formation, even before the starting of the microvasular blood flow. In conclusion, a strong Tie2 promoter activity qualifies as a novel marker of the arteriolar phenotype in microvascular endothelium.

Keywords: Tie2, endothelium, asymmetry, arterioles, venules, angiogenesis, mesentery, adipose tissue

References

  • 1. Moldovan N. I., Current priorities in the research of circulating pre‐endothelial cells, Adv. Exp. Med. Biol., 522: 1–8, 2003. [DOI] [PubMed] [Google Scholar]
  • 2. Aird W. C., Endothelial cell heterogeneity, Crit Care Med., 31: S221–S230, 2003. [DOI] [PubMed] [Google Scholar]
  • 3. Torres‐Vazquez J., Kamei M., Weinstein B. M., Molecular distinction between arteries and veins, Cell Tissue Res., 314: 43–59, 2003. [DOI] [PubMed] [Google Scholar]
  • 4. Othman‐Hassan K., Patel K., Papoutsi M., Rodriguez‐Niedenfuhr M., Christ B., Wilting J., Arterial identity of endothelial cells is controlled by local cues, Dev. Biol., 237: 398–409, 2001. [DOI] [PubMed] [Google Scholar]
  • 5. Yancopoulos G. D., Klagsbrun M., Folkman J., Vasculogenesis, angiogenesis, and growth factors: ephrins enter the fray at the border, Cell, 93: 661–664, 1998. [DOI] [PubMed] [Google Scholar]
  • 6. Hansen‐Smith F., Egginton S., Zhou A. L., Hudlicka O., Growth of arterioles precedes that of capillaries in stretch‐induced angiogenesis in skeletal muscle, Microvasc. Res., 62: 1–14, 2001. [DOI] [PubMed] [Google Scholar]
  • 7. Pesce M., Orlandi A., Iachininoto M. G., Straino S., Torella A. R., Rizzuti V., Pompilio G., Bonanno G., Scambia G., Capogrossi M. C., Myoendothelial Differentiation of Human Umbilical Cord Blood‐Derived Stem Cells in Ischemic Limb Tissues, Circ. Res., 93: E51–E62, 2003. [DOI] [PubMed] [Google Scholar]
  • 8. Wang H. U., Chen Z. F., Anderson D. J., Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin‐B2 and its receptor Eph‐B4, Cell, 93: 741–753, 1998. [DOI] [PubMed] [Google Scholar]
  • 9. Shin D., Garcia‐Cardena G., Hayashi S., Gerety S., Asahara T., Stavrakis G., Isner J., Folkman J., Gimbrone M. A., Jr. , Anderson D. J., Expression of ephrinB2 identifies a stable genetic difference between arterial and venous vascular smooth muscle as well as endothelial cells, and marks subsets of microvessels at sites of adult neovascularization, Dev. Biol., 230: 139–150, 2001. [DOI] [PubMed] [Google Scholar]
  • 10. Gale N. W., Baluk P., Pan L., Kwan M., Holash J., DeChiara T. M., McDonald D. M., Yancopoulos G. D., Ephrin‐B2 selectively marks arterial vessels and neovascularization sites in the adult, with expression in both endothelial and smooth‐ muscle cells, Dev. Biol., 230: 151–160, 2001. [DOI] [PubMed] [Google Scholar]
  • 11. Stalmans I., Ng Y. S., Rohan R., Fruttiger M., Bouche A., Yuce A., Fujisawa H., Hermans B., Shani M., Jansen S., Hicklin D., Anderson D. J., Gardiner T., Hammes H. P., Moons L., Dewerchin M., Collen D., Carmeliet P., D'Amore P. A., Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms, J. Clin. Invest., 109: 327–336, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Shutter J. R., Scully S., Fan W., Richards W. G., Kitajewski J., Deblandre G. A., Kintner C. R., Stark K. L., D114, a novel Notch ligand expressed in arterial endothelium, Genes Dev., 14: 1313–1318, 2000. [PMC free article] [PubMed] [Google Scholar]
  • 13. Rajantie I., Ekman N., Iljin K., Arighi E., Gunji Y., Kaukonen J., Palotie A., Dewerchin M., Carmeliet P., Alitalo K., Bmx tyrosine kinase has a redundant function downstream of angiopoietin and vascular endothelial growth factor receptors in arterial endothelium, Mol. Cell Biol., 21: 4647–4655, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Korhonen J., Lahtinen I., Halmekyto M., Alhonen L., Janne J., Dumont D., Alitalo K., Endothelial‐specific gene expression directed by the tie gene promoter in vivo , Blood, 86: 1828–1835, 1995. [PubMed] [Google Scholar]
  • 15. Schnurch H. Risau W., Expression of tie‐2, a member of a novel family of receptor tyrosine kinases, in the endothelial cell lineage, Development, 119: 957–968, 1993. [DOI] [PubMed] [Google Scholar]
  • 16. Wong A. L., Haroon Z. A., Werner S., Dewhirst M. W., Greenberg C. S., Peters K. G., Tie2 expression and phophorylation in angiogenic and quiescent adult tissues, Circ. Res., 81: 567–574, 1997. [DOI] [PubMed] [Google Scholar]
  • 17. Schlaeger T. M., Bartunkova S., Lawitts J. A., Teichmann G., Risau W., Deutsch U., Sato T. N., Uniform vascular‐endothelial‐cell‐specific gene expression in both embryonic and adult transgenic mice, Proc. Natl. Acad. Sci. U.S.A, 94: 3058–3063, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Dube A., Akbarali Y., Sato T. N., Libermann T. A., Oettgen P., Role of the Ets transcription factors in the regulation of the vascular‐specific Tie2 gene, Circ. Res., 84: 1177–1185, 1999. [DOI] [PubMed] [Google Scholar]
  • 19. Kalka C., Masuda H., Takahashi T., Kalka‐Moll W. M., Silver M., Kearney M., Li T., Isner J. M., Asahara T., Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization, Proc. Natl. Acad. Sci. U. S. A., 97: 3422–3427, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Thurston G., Baluk P., McDonald D. M., Determinants of endothelial cell phenotype in venules, Microcirculation, 7: 67–80, 2000. [PubMed] [Google Scholar]
  • 21. Acarregui M. J., England K. M., Richman J. T., Littig J. L., Characterization of CD34+ cells isolated from human fetal lung, Am. J. Physiol., 284: L395–L401, 2003. [DOI] [PubMed] [Google Scholar]
  • 22. Simper D., Stalboerger P. G., Panetta C. J., Wang S., Caplice N. M., Smooth muscle progenitor cells in human blood, Circulation, 106: 1199–1204, 2002. [DOI] [PubMed] [Google Scholar]
  • 23. Peters K. G., Kontos C. D., Lin P. C., Wong A. L., Rao P., Huang L., Dewhirst M. W., Sankar S., Functional significance of Tie2 signaling in the adult vasculature, Recent Prog. Horm. Res., 59: 51–71, 2004. [DOI] [PubMed] [Google Scholar]
  • 24. Abdulmalek K., Ashur F., Ezer N., Ye F., Magder S., Hussain S. N., Differential expression of Tie‐2 receptors and angiopoietins in response to in vivo hypoxia in rats, Am. J. Physiol., 281: L582–L590, 2001. [DOI] [PubMed] [Google Scholar]
  • 25. Kuroda K., Sapadin A., Shoji T., Fleischmajer R., Lebwohl M., Altered expression of angiopoietins and Tie2 endothelium receptor in psoriasis, J. Invest Dermatol., 116: 713–720, 2001. [DOI] [PubMed] [Google Scholar]
  • 26. Tscheudschilsuren G., Aust G., Nieber K., Schilling N., Spanel‐Borowski K., Microvascular endothelial cells differ in basal and hypoxia‐regulated expression of angiogenic factors and their receptors, Microvasc. Res., 63: 243–251, 2002. [DOI] [PubMed] [Google Scholar]
  • 27. Isner J. M., Kalka C., Kawamoto A., Asahara T., Bone marrow as a source of endothelial cells for natural and iatrogenic vascular repair, Ann. N. Y. Acad. Sci., 953: 75–84, 2001. [DOI] [PubMed] [Google Scholar]
  • 28. Moyon D., Pardanaud L., Yuan L., Breant C., Eichmann A., Plasticity of endothelial cells during arterial‐venous differentiation in the avian embryo, Development, 128: 3359–3370, 2001. [DOI] [PubMed] [Google Scholar]
  • 29. Motoike T., Loughna S., Perens E., Roman B. L., Liao W., Chau T. C., Richardson C. D., Kawate T., Kuno J., Weinstein B. M., Stainier D. Y., Sato T. N., Universal GFP reporter for the study of vascular development, Genesis., 28: 75–81, 2000. [DOI] [PubMed] [Google Scholar]
  • 30. van der Loo B., Fenton M. J., Erusalimsky J. D., Cytochemical detection of a senescence‐associated betagalactosidase in endothelial and smooth muscle cells from human and rabbit blood vessels, Exp. Cell Res., 241: 309–315, 1998. [DOI] [PubMed] [Google Scholar]
  • 31. 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–H2562, 1996. [DOI] [PubMed] [Google Scholar]
  • 32. Norrby K., Jakobsson A., Sorbo J., Quantitative angiogenesis in spreads of intact rat mesenteric windows, Microvasc. Res., 39: 341–348, 1990. [DOI] [PubMed] [Google Scholar]
  • 33. Norrby K., Basic fibroblast growth factor and de novo mammalian angiogenesis, Microvasc. Res., 48: 96–113, 1994. [DOI] [PubMed] [Google Scholar]
  • 34. Norrby K., Vascular endothelial growth factor and de novo mammalian angiogenesis, Microvasc. Res., 51: 153–163, 1996. [DOI] [PubMed] [Google Scholar]
  • 35. Crandall D. L., Hausman G. J., Kral J. G., A review of the microcirculation of adipose tissue: anatomic, metabolic, and angiogenic perspectives, Microcirculation, 4: 211–232, 1997. [DOI] [PubMed] [Google Scholar]
  • 36. Planat‐Benard V., Silvestre J. S., Cousin B., Andre M., Nibbelink M., Tamarat R., Clergue M., Manneville C., Saillan‐Barreau C., Duriez M., Tedgui A., Levy B., Penicaud L., Casteilla L., Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives, Circulation, 109: 656–663, 2004. [DOI] [PubMed] [Google Scholar]
  • 37. Simionescu N., Simionescu M., Palade G. E., Structural basis of permeability in sequential segments of the microvasculature of the diaphragm. I. Bipolar microvascular fields, Microvasc. Res., 15: 1–16, 1978. [DOI] [PubMed] [Google Scholar]
  • 38. Ismail J. A., Poppa V., Kemper L. E., Scatena M., Giachelli C. M., Coffin J. D., Murry C. E., Immunohistologic labeling of murine endothelium, Cardiovasc. Pathol., 12: 82–90, 2003. [DOI] [PubMed] [Google Scholar]
  • 39. Suri C., McClain J., Thurston G., McDonald D. M., Zhou H., Oldmixon E. H., Sato T. N., Yancopoulos G. D., Increased vascularization in mice overexpressing angiopoietin‐1, Science, 282: 468–471, 1998. [DOI] [PubMed] [Google Scholar]
  • 40. Ward N. L. Dumont D. J., The angiopoietins and Tie2/Tek: adding to the complexity of cardiovascular development, Semin. Cell Dev. Biol., 13: 19–27, 2002. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Cellular and Molecular Medicine are provided here courtesy of Blackwell Publishing

RESOURCES