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. 1993 Oct 1;90(19):8915–8919. doi: 10.1073/pnas.90.19.8915

Vascular endothelial growth factor receptor expression during embryogenesis and tissue repair suggests a role in endothelial differentiation and blood vessel growth.

K G Peters 1, C De Vries 1, L T Williams 1
PMCID: PMC47471  PMID: 7692439

Abstract

Vascular endothelial growth factor (VEGF) is a polypeptide mitogen that stimulates the growth of endothelial cells in vitro and promotes the growth of blood vessels in vivo. We have recently shown that the fms-like receptor tyrosine kinase (flt) is a receptor for VEGF. Here we used in situ hybridization to show that, in adult mouse tissues, the pattern of flt expression was consistent with localization in endothelium. We also show that flt was expressed in endothelium during neovascularization of healing skin wounds and during early vascular development in mouse embryos. Moreover, flt was expressed in populations of embryonic cells from which endothelium is derived such as early yolk sac mesenchyme. The expression of flt in the endothelium of both developing and mature blood vessels suggests that VEGF might regulate endothelial differentiation, blood vessel growth, and vascular repair.

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Selected References

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

  1. Breier G., Albrecht U., Sterrer S., Risau W. Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development. 1992 Feb;114(2):521–532. doi: 10.1242/dev.114.2.521. [DOI] [PubMed] [Google Scholar]
  2. Brown L. F., Yeo K. T., Berse B., Yeo T. K., Senger D. R., Dvorak H. F., van de Water L. Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing. J Exp Med. 1992 Nov 1;176(5):1375–1379. doi: 10.1084/jem.176.5.1375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. Conn G., Bayne M. L., Soderman D. D., Kwok P. W., Sullivan K. A., Palisi T. M., Hope D. A., Thomas K. A. Amino acid and cDNA sequences of a vascular endothelial cell mitogen that is homologous to platelet-derived growth factor. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2628–2632. doi: 10.1073/pnas.87.7.2628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Connolly D. T., Heuvelman D. M., Nelson R., Olander J. V., Eppley B. L., Delfino J. J., Siegel N. R., Leimgruber R. M., Feder J. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest. 1989 Nov;84(5):1470–1478. doi: 10.1172/JCI114322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Connolly D. T. Vascular permeability factor: a unique regulator of blood vessel function. J Cell Biochem. 1991 Nov;47(3):219–223. doi: 10.1002/jcb.240470306. [DOI] [PubMed] [Google Scholar]
  7. Ferrara N., Henzel W. J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989 Jun 15;161(2):851–858. doi: 10.1016/0006-291x(89)92678-8. [DOI] [PubMed] [Google Scholar]
  8. Ferrara N., Houck K. A., Jakeman L. B., Winer J., Leung D. W. The vascular endothelial growth factor family of polypeptides. J Cell Biochem. 1991 Nov;47(3):211–218. doi: 10.1002/jcb.240470305. [DOI] [PubMed] [Google Scholar]
  9. Frohman M. A., Boyle M., Martin G. R. Isolation of the mouse Hox-2.9 gene; analysis of embryonic expression suggests that positional information along the anterior-posterior axis is specified by mesoderm. Development. 1990 Oct;110(2):589–607. doi: 10.1242/dev.110.2.589. [DOI] [PubMed] [Google Scholar]
  10. Galland F., Karamysheva A., Mattei M. G., Rosnet O., Marchetto S., Birnbaum D. Chromosomal localization of FLT4, a novel receptor-type tyrosine kinase gene. Genomics. 1992 Jun;13(2):475–478. doi: 10.1016/0888-7543(92)90277-y. [DOI] [PubMed] [Google Scholar]
  11. Gospodarowicz D., Abraham J. A., Schilling J. Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7311–7315. doi: 10.1073/pnas.86.19.7311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gospodarowicz D. Fibroblast growth factor and its involvement in developmental processes. Curr Top Dev Biol. 1990;24:57–93. doi: 10.1016/s0070-2153(08)60084-8. [DOI] [PubMed] [Google Scholar]
  13. Jakeman L. B., Winer J., Bennett G. L., Altar C. A., Ferrara N. Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. J Clin Invest. 1992 Jan;89(1):244–253. doi: 10.1172/JCI115568. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Keck P. J., Hauser S. D., Krivi G., Sanzo K., Warren T., Feder J., Connolly D. T. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989 Dec 8;246(4935):1309–1312. doi: 10.1126/science.2479987. [DOI] [PubMed] [Google Scholar]
  15. Leung D. W., Cachianes G., Kuang W. J., Goeddel D. V., Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989 Dec 8;246(4935):1306–1309. doi: 10.1126/science.2479986. [DOI] [PubMed] [Google Scholar]
  16. Matsushime H., Yoshida M. C., Sasaki M., Shibuya M. A possible new member of tyrosine kinase family, human frt sequence, is highly conserved in vertebrates and located on human chromosome 13. Jpn J Cancer Res. 1987 Jul;78(7):655–661. [PubMed] [Google Scholar]
  17. Matthews W., Jordan C. T., Gavin M., Jenkins N. A., Copeland N. G., Lemischka I. R. A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hematopoietic cells and exhibiting close genetic linkage to c-kit. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9026–9030. doi: 10.1073/pnas.88.20.9026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Melton D. A., Krieg P. A., Rebagliati M. R., Maniatis T., Zinn K., Green M. R. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056. doi: 10.1093/nar/12.18.7035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Millauer B., Wizigmann-Voos S., Schnürch H., Martinez R., Møller N. P., Risau W., Ullrich A. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell. 1993 Mar 26;72(6):835–846. doi: 10.1016/0092-8674(93)90573-9. [DOI] [PubMed] [Google Scholar]
  20. Noden D. M. Embryonic origins and assembly of blood vessels. Am Rev Respir Dis. 1989 Oct;140(4):1097–1103. doi: 10.1164/ajrccm/140.4.1097. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Plouët J., Schilling J., Gospodarowicz D. Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT-20 cells. EMBO J. 1989 Dec 1;8(12):3801–3806. doi: 10.1002/j.1460-2075.1989.tb08557.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Quinn T. P., Peters K. G., De Vries C., Ferrara N., Williams L. T. Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7533–7537. doi: 10.1073/pnas.90.16.7533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Senger D. R., Connolly D. T., Van de Water L., Feder J., Dvorak H. F. Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res. 1990 Mar 15;50(6):1774–1778. [PubMed] [Google Scholar]
  25. Shibuya M., Yamaguchi S., Yamane A., Ikeda T., Tojo A., Matsushime H., Sato M. Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene. 1990 Apr;5(4):519–524. [PubMed] [Google Scholar]
  26. Stemple D. L., Mahanthappa N. K., Anderson D. J. Basic FGF induces neuronal differentiation, cell division, and NGF dependence in chromaffin cells: a sequence of events in sympathetic development. Neuron. 1988 Aug;1(6):517–525. doi: 10.1016/0896-6273(88)90182-1. [DOI] [PubMed] [Google Scholar]
  27. Terman B. I., Carrion M. E., Kovacs E., Rasmussen B. A., Eddy R. L., Shows T. B. Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene. 1991 Sep;6(9):1677–1683. [PubMed] [Google Scholar]
  28. Terman B. I., Dougher-Vermazen M., Carrion M. E., Dimitrov D., Armellino D. C., Gospodarowicz D., Böhlen P. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun. 1992 Sep 30;187(3):1579–1586. doi: 10.1016/0006-291x(92)90483-2. [DOI] [PubMed] [Google Scholar]
  29. Tischer E., Gospodarowicz D., Mitchell R., Silva M., Schilling J., Lau K., Crisp T., Fiddes J. C., Abraham J. A. Vascular endothelial growth factor: a new member of the platelet-derived growth factor gene family. Biochem Biophys Res Commun. 1989 Dec 29;165(3):1198–1206. doi: 10.1016/0006-291x(89)92729-0. [DOI] [PubMed] [Google Scholar]
  30. Warburton D., Seth R., Shum L., Horcher P. G., Hall F. L., Werb Z., Slavkin H. C. Epigenetic role of epidermal growth factor expression and signalling in embryonic mouse lung morphogenesis. Dev Biol. 1992 Jan;149(1):123–133. doi: 10.1016/0012-1606(92)90269-m. [DOI] [PubMed] [Google Scholar]
  31. Wilcox J. N., Smith K. M., Williams L. T., Schwartz S. M., Gordon D. Platelet-derived growth factor mRNA detection in human atherosclerotic plaques by in situ hybridization. J Clin Invest. 1988 Sep;82(3):1134–1143. doi: 10.1172/JCI113671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Wilkinson D. G., Bailes J. A., Champion J. E., McMahon A. P. A molecular analysis of mouse development from 8 to 10 days post coitum detects changes only in embryonic globin expression. Development. 1987 Apr;99(4):493–500. doi: 10.1242/dev.99.4.493. [DOI] [PubMed] [Google Scholar]
  33. 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]

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