Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1990 Aug;87(15):5978–5982. doi: 10.1073/pnas.87.15.5978

Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells.

A Anagnostou 1, E S Lee 1, N Kessimian 1, R Levinson 1, M Steiner 1
PMCID: PMC54453  PMID: 2165612

Abstract

Erythropoietin is known to be a hematopoietic growth factor with a singularly specific action on the proliferation and differentiation of erythroid progenitor cells. We have observed a dose-dependent proliferative action of human recombinant erythropoietin on human umbilical vein endothelial cells and bovine adrenal capillary endothelial cells. Binding studies with radioiodinated recombinant human erythropoietin revealed a large number (approximately 27,000) of an apparent single class of receptors with an affinity in the 10(-9) M range. Linkage of the radiolabeled ligand to its receptor via a bifunctional crosslinking agent allowed us to identify an endothelial cell protein of 45 kDa as the principal receptor associated with this mitogenic effect of erythropoietin. Recombinant human erythropoietin also enhanced the migration of endothelial cells.

Full text

PDF
5978

Images in this article

Selected References

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

  1. Ascensao J. L., Vercellotti G. M., Jacob H. S., Zanjani E. D. Role of endothelial cells in human hematopoiesis: modulation of mixed colony growth in vitro. Blood. 1984 Mar;63(3):553–558. [PubMed] [Google Scholar]
  2. Berdel W. E., Danhauser-Riedl S., Steinhauser G., Winton E. F. Various human hematopoietic growth factors (interleukin-3, GM-CSF, G-CSF) stimulate clonal growth of nonhematopoietic tumor cells. Blood. 1989 Jan;73(1):80–83. [PubMed] [Google Scholar]
  3. Boussios T., Bertles J. F., Goldwasser E. Erythropoietin. Receptor characteristics during the ontogeny of hamster yolk sac erythroid cells. J Biol Chem. 1989 Sep 25;264(27):16017–16021. [PubMed] [Google Scholar]
  4. Broudy V. C., Lin N., Egrie J., de Haën C., Weiss T., Papayannopoulou T., Adamson J. W. Identification of the receptor for erythropoietin on human and murine erythroleukemia cells and modulation by phorbol ester and dimethyl sulfoxide. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6513–6517. doi: 10.1073/pnas.85.17.6513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bussolino F., Wang J. M., Defilippi P., Turrini F., Sanavio F., Edgell C. J., Aglietta M., Arese P., Mantovani A. Granulocyte- and granulocyte-macrophage-colony stimulating factors induce human endothelial cells to migrate and proliferate. Nature. 1989 Feb 2;337(6206):471–473. doi: 10.1038/337471a0. [DOI] [PubMed] [Google Scholar]
  6. Connolly D. T., Stoddard B. L., Harakas N. K., Feder J. Human fibroblast-derived growth factor is a mitogen and chemoattractant for endothelial cells. Biochem Biophys Res Commun. 1987 Apr 29;144(2):705–712. doi: 10.1016/s0006-291x(87)80022-0. [DOI] [PubMed] [Google Scholar]
  7. Dainiak N., Warren H. B., Kreczko S., Riordan M. A., Feldman L., Lawler J., Cohen A. M., Davies P. F. Acetylated lipoproteins impair erythroid growth factor release from endothelial cells. J Clin Invest. 1988 Mar;81(3):834–843. doi: 10.1172/JCI113392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dedhar S., Gaboury L., Galloway P., Eaves C. Human granulocyte-macrophage colony-stimulating factor is a growth factor active on a variety of cell types of nonhemopoietic origin. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9253–9257. doi: 10.1073/pnas.85.23.9253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dejana E., Languino L. R., Polentarutti N., Balconi G., Ryckewaert J. J., Larrieu M. J., Donati M. B., Mantovani A., Marguerie G. Interaction between fibrinogen and cultured endothelial cells. Induction of migration and specific binding. J Clin Invest. 1985 Jan;75(1):11–18. doi: 10.1172/JCI111661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Folkman J., Haudenschild C. C., Zetter B. R. Long-term culture of capillary endothelial cells. Proc Natl Acad Sci U S A. 1979 Oct;76(10):5217–5221. doi: 10.1073/pnas.76.10.5217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Folkman J., Klagsbrun M. Angiogenic factors. Science. 1987 Jan 23;235(4787):442–447. doi: 10.1126/science.2432664. [DOI] [PubMed] [Google Scholar]
  12. Folkman J. Tumor angiogenesis. Adv Cancer Res. 1974;19(0):331–358. doi: 10.1016/s0065-230x(08)60058-5. [DOI] [PubMed] [Google Scholar]
  13. Fraser J. K., Nicholls J., Coffey C., Lin F. K., Berridge M. V. Down-modulation of high-affinity receptors for erythropoietin on murine erythroblasts by interleukin 3. Exp Hematol. 1988 Oct;16(9):769–773. [PubMed] [Google Scholar]
  14. Fraser J. K., Tan A. S., Lin F. K., Berridge M. V. Expression of specific high-affinity binding sites for erythropoietin on rat and mouse megakaryocytes. Exp Hematol. 1989 Jan;17(1):10–16. [PubMed] [Google Scholar]
  15. Fukamachi H., Saito T., Tojo A., Kitamura T., Urabe A., Takaku F. Binding of erythropoietin to CFU-E derived from fetal mouse liver cells. Exp Hematol. 1987 Sep;15(8):833–837. [PubMed] [Google Scholar]
  16. Galelli A., Dosne A. M., Morin A., Dubor F., Chedid L. Stimulation of human endothelial cells by synthetic muramyl peptides: production of colony-stimulating activity (CSA). Exp Hematol. 1985 Dec;13(11):1157–1163. [PubMed] [Google Scholar]
  17. Ganser A., Bergmann M., Völkers B., Grützmacher P., Scigalla P., Hoelzer D. In vivo effects of recombinant human erythropoietin on circulating human hemopoietic progenitor cells. Exp Hematol. 1989 Jun;17(5):433–435. [PubMed] [Google Scholar]
  18. Gordon M. Y., Kearney L., Hibbin J. A. Effects of human marrow stromal cells on proliferation by human granulocytic (GM-CFC), erythroid (BFU-E) and mixed (Mix-CFC) colony-forming cells. Br J Haematol. 1983 Feb;53(2):317–325. doi: 10.1111/j.1365-2141.1983.tb02026.x. [DOI] [PubMed] [Google Scholar]
  19. Graber S. E., Krantz S. B. Erythropoietin: biology and clinical use. Hematol Oncol Clin North Am. 1989 Sep;3(3):369–400. [PubMed] [Google Scholar]
  20. Heldin C. H., Westermark B., Wasteson A. Specific receptors for platelet-derived growth factor on cells derived from connective tissue and glia. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3664–3668. doi: 10.1073/pnas.78.6.3664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Krantz S. B., Sawyer S. T., Sawada K. I. Purification of erythroid progenitor cells and characterization of erythropoietin receptors. Br J Cancer Suppl. 1988 Dec;9:31–35. [PMC free article] [PubMed] [Google Scholar]
  22. Leiter A. B., Toder A., Wolfe H. J., Taylor I. L., Cooperman S., Mandel G., Goodman R. H. Peptide YY. Structure of the precursor and expression in exocrine pancreas. J Biol Chem. 1987 Sep 25;262(27):12984–12988. [PubMed] [Google Scholar]
  23. Means R. T., Jr, Krantz S. B., Sawyer S. T., Gilbert H. S. Erythropoietin receptors in polycythemia vera. J Clin Invest. 1989 Oct;84(4):1340–1344. doi: 10.1172/JCI114303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Metcalf D. Haemopoietic growth factors 1. Lancet. 1989 Apr 15;1(8642):825–827. doi: 10.1016/s0140-6736(89)92280-0. [DOI] [PubMed] [Google Scholar]
  25. Pekonen F., Rosenlöf K., Rutanen E. M., Fyhrquist F. Erythropoietin binding sites in human foetal tissues. Acta Endocrinol (Copenh) 1987 Dec;116(4):561–567. doi: 10.1530/acta.0.1160561. [DOI] [PubMed] [Google Scholar]
  26. Quesenberry P. J., Gimbrone M. A., Jr Vascular endothelium as a regulator of granulopoiesis: production of colony-stimulating activity by cultured human endothelial cells. Blood. 1980 Dec;56(6):1060–1067. [PubMed] [Google Scholar]
  27. Raine A. E. Hypertension, blood viscosity, and cardiovascular morbidity in renal failure: implications of erythropoietin therapy. Lancet. 1988 Jan 16;1(8577):97–100. doi: 10.1016/s0140-6736(88)90293-0. [DOI] [PubMed] [Google Scholar]
  28. Sasaki H., Bothner B., Dell A., Fukuda M. Carbohydrate structure of erythropoietin expressed in Chinese hamster ovary cells by a human erythropoietin cDNA. J Biol Chem. 1987 Sep 5;262(25):12059–12076. [PubMed] [Google Scholar]
  29. Sasaki R., Yanagawa S., Hitomi K., Chiba H. Characterization of erythropoietin receptor of murine erythroid cells. Eur J Biochem. 1987 Oct 1;168(1):43–48. doi: 10.1111/j.1432-1033.1987.tb13384.x. [DOI] [PubMed] [Google Scholar]
  30. Sawyer S. T., Krantz S. B., Goldwasser E. Binding and receptor-mediated endocytosis of erythropoietin in Friend virus-infected erythroid cells. J Biol Chem. 1987 Apr 25;262(12):5554–5562. [PubMed] [Google Scholar]
  31. Sawyer S. T., Krantz S. B., Sawada K. Receptors for erythropoietin in mouse and human erythroid cells and placenta. Blood. 1989 Jul;74(1):103–109. [PubMed] [Google Scholar]
  32. Takeuchi M., Takasaki S., Miyazaki H., Kato T., Hoshi S., Kochibe N., Kobata A. Comparative study of the asparagine-linked sugar chains of human erythropoietins purified from urine and the culture medium of recombinant Chinese hamster ovary cells. J Biol Chem. 1988 Mar 15;263(8):3657–3663. [PubMed] [Google Scholar]
  33. Todokoro K., Kanazawa S., Amanuma H., Ikawa Y. Specific binding of erythropoietin to its receptor on responsive mouse erythroleukemia cells. Proc Natl Acad Sci U S A. 1987 Jun;84(12):4126–4130. doi: 10.1073/pnas.84.12.4126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Tojo A., Fukamachi H., Kasuga M., Urabe A., Takaku F. Identification of erythropoietin receptors on fetal liver erythroid cells. Biochem Biophys Res Commun. 1987 Oct 14;148(1):443–448. doi: 10.1016/0006-291x(87)91131-4. [DOI] [PubMed] [Google Scholar]
  35. Tsao C. J., Tojo A., Fukamachi H., Kitamura T., Saito T., Urabe A., Takaku F. Expression of the functional erythropoietin receptors on interleukin 3-dependent murine cell lines. J Immunol. 1988 Jan 1;140(1):89–93. [PubMed] [Google Scholar]
  36. Vancura S., Steiner M. Identification of Fc and F(ab')2 IgG receptors on human platelets. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3575–3579. doi: 10.1073/pnas.84.11.3575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Veomett G., Kuszynski C., Kazakoff P., Rizzino A. Cell density regulates the number of cell surface receptors for fibroblast growth factor. Biochem Biophys Res Commun. 1989 Mar 15;159(2):694–700. doi: 10.1016/0006-291x(89)90050-8. [DOI] [PubMed] [Google Scholar]
  38. van Hinsbergh V. W., Mommaas-Kienhuis A. M., Weinstein R., Maciag T. Propagation and morphologic phenotypes of human umbilical cord artery endothelial cells. Eur J Cell Biol. 1986 Oct;42(1):101–110. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES