Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1995 Dec 1;14(23):5884–5891. doi: 10.1002/j.1460-2075.1995.tb00276.x

The receptor tyrosine kinase TIE is required for integrity and survival of vascular endothelial cells.

M C Puri 1, J Rossant 1, K Alitalo 1, A Bernstein 1, J Partanen 1
PMCID: PMC394706  PMID: 8846781

Abstract

Vascular endothelial cells are critical for the development and function of the mammalian circulatory system. We have analyzed the role of the endothelial cell-specific receptor tyrosine kinase TIE in the mouse vasculature. Mouse embryos homozygous for a disrupted Tie allele developed severe edema, their microvasculature was ruptured and they died between days 13.5 and 14.5 of gestation. The major blood vessels of the homozygous embryos appeared normal. Cells lacking a functional Tie gene were unable to contribute to the adult kidney endothelium in chimeric animals, further demonstrating the intrinsic requirement for TIE in endothelial cells. We conclude that TIE is required during embryonic development for the integrity and survival of vascular endothelial cells, particularly in the regions undergoing angiogenic growth of capillaries. TIE is not essential, however, for vasculogenesis, the early differentiation of endothelial cells.

Full text

PDF
5885

Images in this article

5886Image
on p.5886
5887Image
on p.5887
5888Image
on p.5888
5889Image
on p.5889

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Armstrong E., Korhonen J., Silvennoinen O., Cleveland J. L., Lieberman M. A., Alitalo R. Expression of tie receptor tyrosine kinase in leukemia cell lines. Leukemia. 1993 Oct;7(10):1585–1591. [PubMed] [Google Scholar]
  2. Coffin J. D., Harrison J., Schwartz S., Heimark R. Angioblast differentiation and morphogenesis of the vascular endothelium in the mouse embryo. Dev Biol. 1991 Nov;148(1):51–62. doi: 10.1016/0012-1606(91)90316-u. [DOI] [PubMed] [Google Scholar]
  3. Coffin J. D., Poole T. J. Embryonic vascular development: immunohistochemical identification of the origin and subsequent morphogenesis of the major vessel primordia in quail embryos. Development. 1988 Apr;102(4):735–748. doi: 10.1242/dev.102.4.735. [DOI] [PubMed] [Google Scholar]
  4. Dumont D. J., Fong G. H., Puri M. C., Gradwohl G., Alitalo K., Breitman M. L. Vascularization of the mouse embryo: a study of flk-1, tek, tie, and vascular endothelial growth factor expression during development. Dev Dyn. 1995 May;203(1):80–92. doi: 10.1002/aja.1002030109. [DOI] [PubMed] [Google Scholar]
  5. Dumont D. J., Gradwohl G., Fong G. H., Puri M. C., Gertsenstein M., Auerbach A., Breitman M. L. Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev. 1994 Aug 15;8(16):1897–1909. doi: 10.1101/gad.8.16.1897. [DOI] [PubMed] [Google Scholar]
  6. Dumont D. J., Yamaguchi T. P., Conlon R. A., Rossant J., Breitman M. L. tek, a novel tyrosine kinase gene located on mouse chromosome 4, is expressed in endothelial cells and their presumptive precursors. Oncogene. 1992 Aug;7(8):1471–1480. [PubMed] [Google Scholar]
  7. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995 Jan;1(1):27–31. doi: 10.1038/nm0195-27. [DOI] [PubMed] [Google Scholar]
  8. Fong G. H., Rossant J., Gertsenstein M., Breitman M. L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature. 1995 Jul 6;376(6535):66–70. doi: 10.1038/376066a0. [DOI] [PubMed] [Google Scholar]
  9. Hatva E., Kaipainen A., Mentula P., Jäskeläinen J., Paetau A., Haltia M., Alitalo K. Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors. Am J Pathol. 1995 Feb;146(2):368–378. [PMC free article] [PubMed] [Google Scholar]
  10. Iwama A., Hamaguchi I., Hashiyama M., Murayama Y., Yasunaga K., Suda T. Molecular cloning and characterization of mouse TIE and TEK receptor tyrosine kinase genes and their expression in hematopoietic stem cells. Biochem Biophys Res Commun. 1993 Aug 31;195(1):301–309. doi: 10.1006/bbrc.1993.2045. [DOI] [PubMed] [Google Scholar]
  11. Kaipainen A., Vlaykova T., Hatva E., Böhling T., Jekunen A., Pyrhönen S., Alitalo K. Enhanced expression of the tie receptor tyrosine kinase mesenger RNA in the vascular endothelium of metastatic melanomas. Cancer Res. 1994 Dec 15;54(24):6571–6577. [PubMed] [Google Scholar]
  12. Korhonen J., Lahtinen I., Halmekytö M., Alhonen L., Jänne J., Dumont D., Alitalo K. Endothelial-specific gene expression directed by the tie gene promoter in vivo. Blood. 1995 Sep 1;86(5):1828–1835. [PubMed] [Google Scholar]
  13. Korhonen J., Partanen J., Armstrong E., Vaahtokari A., Elenius K., Jalkanen M., Alitalo K. Enhanced expression of the tie receptor tyrosine kinase in endothelial cells during neovascularization. Blood. 1992 Nov 15;80(10):2548–2555. [PubMed] [Google Scholar]
  14. Korhonen J., Polvi A., Partanen J., Alitalo K. The mouse tie receptor tyrosine kinase gene: expression during embryonic angiogenesis. Oncogene. 1994 Feb;9(2):395–403. [PubMed] [Google Scholar]
  15. Maisonpierre P. C., Goldfarb M., Yancopoulos G. D., Gao G. Distinct rat genes with related profiles of expression define a TIE receptor tyrosine kinase family. Oncogene. 1993 Jun;8(6):1631–1637. [PubMed] [Google Scholar]
  16. Mansour S. L., Thomas K. R., Capecchi M. R. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature. 1988 Nov 24;336(6197):348–352. doi: 10.1038/336348a0. [DOI] [PubMed] [Google Scholar]
  17. Mustonen T., Alitalo K. Endothelial receptor tyrosine kinases involved in angiogenesis. J Cell Biol. 1995 May;129(4):895–898. doi: 10.1083/jcb.129.4.895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Nagy A., Rossant J., Nagy R., Abramow-Newerly W., Roder J. C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8424–8428. doi: 10.1073/pnas.90.18.8424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Pardanaud L., Altmann C., Kitos P., Dieterlen-Lievre F., Buck C. A. Vasculogenesis in the early quail blastodisc as studied with a monoclonal antibody recognizing endothelial cells. Development. 1987 Jun;100(2):339–349. doi: 10.1242/dev.100.2.339. [DOI] [PubMed] [Google Scholar]
  20. Pardanaud L., Yassine F., Dieterlen-Lievre F. Relationship between vasculogenesis, angiogenesis and haemopoiesis during avian ontogeny. Development. 1989 Mar;105(3):473–485. doi: 10.1242/dev.105.3.473. [DOI] [PubMed] [Google Scholar]
  21. Partanen J., Armstrong E., Mäkelä T. P., Korhonen J., Sandberg M., Renkonen R., Knuutila S., Huebner K., Alitalo K. A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol Cell Biol. 1992 Apr;12(4):1698–1707. doi: 10.1128/mcb.12.4.1698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Sariola H., Peault B., LeDouarin N., Buck C., Dieterlen-Lièvre F., Saxén L. Extracellular matrix and capillary ingrowth in interspecies chimeric kidneys. Cell Differ. 1984 Nov;15(1):43–51. doi: 10.1016/0045-6039(84)90028-9. [DOI] [PubMed] [Google Scholar]
  23. Sato T. N., Qin Y., Kozak C. A., Audus K. L. Tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9355–9358. doi: 10.1073/pnas.90.20.9355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Sauer B. Manipulation of transgenes by site-specific recombination: use of Cre recombinase. Methods Enzymol. 1993;225:890–900. doi: 10.1016/0076-6879(93)25056-8. [DOI] [PubMed] [Google Scholar]
  25. Shalaby F., Rossant J., Yamaguchi T. P., Gertsenstein M., Wu X. F., Breitman M. L., Schuh A. C. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995 Jul 6;376(6535):62–66. doi: 10.1038/376062a0. [DOI] [PubMed] [Google Scholar]
  26. Wood S. A., Allen N. D., Rossant J., Auerbach A., Nagy A. Non-injection methods for the production of embryonic stem cell-embryo chimaeras. Nature. 1993 Sep 2;365(6441):87–89. doi: 10.1038/365087a0. [DOI] [PubMed] [Google Scholar]
  27. Yamaguchi T. P., Dumont D. J., Conlon R. A., Breitman M. L., Rossant J. flk-1, an flt-related receptor tyrosine kinase is an early marker for endothelial cell precursors. Development. 1993 Jun;118(2):489–498. doi: 10.1242/dev.118.2.489. [DOI] [PubMed] [Google Scholar]
  28. de Vries C., Escobedo J. A., Ueno H., Houck K., Ferrara N., Williams L. T. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 1992 Feb 21;255(5047):989–991. doi: 10.1126/science.1312256. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES