Abstract
The growth factor receptors expressed on endothelial cells are of special interest because of their potential to program endothelial cell growth and differentiation during development and neovascularization in various pathological states, such as wound healing and angiogenesis associated with tumorigenesis. Vascular endothelial growth factor ([VEGF] also known as vascular permeability factor) is a potent mitogen and permeability factor, which has been suggested to play a role in embryonic and tumor angiogenesis. The newly cloned FLT4 receptor tyrosine kinase gene encodes a protein related to the VEGF receptors FLT1 and KDR/FLK-1. We have here studied the expression of FLT4 and the other two members of this receptor family in human fetal tissues by Northern and in situ hybridization. These results were also compared with the sites of expression of VEGF and the related placenta growth factor (PlGF). Our results reveal FLT4 mRNA expression in vascular endothelial cells in developing vessels of several organs. A comparison of FLT4, FLT1 and KDR/FLK-1 receptor mRNA signals shows overlapping, but distinct expression patterns in the tissues studied. Certain endothelia lack one or two of the three receptor mRNAs. These data suggest that the receptor tyrosine kinases encoded by the FLT gene family may have distinct functions in the regulation of the growth/differentiation of blood vessels.
Full Text
The Full Text of this article is available as a PDF (1.8 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Aprelikova O., Pajusola K., Partanen J., Armstrong E., Alitalo R., Bailey S. K., McMahon J., Wasmuth J., Huebner K., Alitalo K. FLT4, a novel class III receptor tyrosine kinase in chromosome 5q33-qter. Cancer Res. 1992 Feb 1;52(3):746–748. [PubMed] [Google Scholar]
- Berkman R. A., Merrill M. J., Reinhold W. C., Monacci W. T., Saxena A., Clark W. C., Robertson J. T., Ali I. U., Oldfield E. H. Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. J Clin Invest. 1993 Jan;91(1):153–159. doi: 10.1172/JCI116165. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Berse B., Brown L. F., Van de Water L., Dvorak H. F., Senger D. R. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell. 1992 Feb;3(2):211–220. doi: 10.1091/mbc.3.2.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bonthron D., Orr E. C., Mitsock L. M., Ginsburg D., Handin R. I., Orkin S. H. Nucleotide sequence of pre-pro-von Willebrand factor cDNA. Nucleic Acids Res. 1986 Sep 11;14(17):7125–7127. doi: 10.1093/nar/14.17.7125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- 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]
- Charnock E. L., Doershuk C. F. Developmental aspects of the human lung. Pediatr Clin North Am. 1973 May;20(2):275–292. doi: 10.1016/s0031-3955(16)32843-7. [DOI] [PubMed] [Google Scholar]
- Conn G., Soderman D. D., Schaeffer M. T., Wile M., Hatcher V. B., Thomas K. A. Purification of a glycoprotein vascular endothelial cell mitogen from a rat glioma-derived cell line. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1323–1327. doi: 10.1073/pnas.87.4.1323. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Eichmann A., Marcelle C., Bréant C., Le Douarin N. M. Two molecules related to the VEGF receptor are expressed in early endothelial cells during avian embryonic development. Mech Dev. 1993 Jul;42(1-2):33–48. doi: 10.1016/0925-4773(93)90096-g. [DOI] [PubMed] [Google Scholar]
- Fajardo L. F. The complexity of endothelial cells. A review. Am J Clin Pathol. 1989 Aug;92(2):241–250. doi: 10.1093/ajcp/92.2.241. [DOI] [PubMed] [Google Scholar]
- Ferrara N., Houck K., Jakeman L., Leung D. W. Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev. 1992 Feb;13(1):18–32. doi: 10.1210/edrv-13-1-18. [DOI] [PubMed] [Google Scholar]
- Folkman J., Klagsbrun M. Angiogenic factors. Science. 1987 Jan 23;235(4787):442–447. doi: 10.1126/science.2432664. [DOI] [PubMed] [Google Scholar]
- Folkman J., Shing Y. Angiogenesis. J Biol Chem. 1992 Jun 5;267(16):10931–10934. [PubMed] [Google Scholar]
- 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]
- Galland F., Karamysheva A., Pebusque M. J., Borg J. P., Rottapel R., Dubreuil P., Rosnet O., Birnbaum D. The FLT4 gene encodes a transmembrane tyrosine kinase related to the vascular endothelial growth factor receptor. Oncogene. 1993 May;8(5):1233–1240. [PubMed] [Google Scholar]
- 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]
- Hart C. E., Forstrom J. W., Kelly J. D., Seifert R. A., Smith R. A., Ross R., Murray M. J., Bowen-Pope D. F. Two classes of PDGF receptor recognize different isoforms of PDGF. Science. 1988 Jun 10;240(4858):1529–1531. doi: 10.1126/science.2836952. [DOI] [PubMed] [Google Scholar]
- Heldin C. H., Bäckström G., Ostman A., Hammacher A., Rönnstrand L., Rubin K., Nistér M., Westermark B. Binding of different dimeric forms of PDGF to human fibroblasts: evidence for two separate receptor types. EMBO J. 1988 May;7(5):1387–1393. doi: 10.1002/j.1460-2075.1988.tb02955.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jaffe E. A. Cell biology of endothelial cells. Hum Pathol. 1987 Mar;18(3):234–239. doi: 10.1016/s0046-8177(87)80005-9. [DOI] [PubMed] [Google Scholar]
- Jaffe E. A., Hoyer L. W., Nachman R. L. Synthesis of von Willebrand factor by cultured human endothelial cells. Proc Natl Acad Sci U S A. 1974 May;71(5):1906–1909. doi: 10.1073/pnas.71.5.1906. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Klagsbrun M., D'Amore P. A. Regulators of angiogenesis. Annu Rev Physiol. 1991;53:217–239. doi: 10.1146/annurev.ph.53.030191.001245. [DOI] [PubMed] [Google Scholar]
- 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]
- Maglione D., Guerriero V., Viglietto G., Delli-Bovi P., Persico M. G. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9267–9271. doi: 10.1073/pnas.88.20.9267. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Maglione D., Guerriero V., Viglietto G., Ferraro M. G., Aprelikova O., Alitalo K., Del Vecchio S., Lei K. J., Chou J. Y., Persico M. G. Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14. Oncogene. 1993 Apr;8(4):925–931. [PubMed] [Google Scholar]
- 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]
- 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]
- Munsick R. A. Human fetal extremity lengths in the interval from 9 to 21 menstrual weeks of pregnancy. Am J Obstet Gynecol. 1984 Aug 15;149(8):883–887. doi: 10.1016/0002-9378(84)90609-4. [DOI] [PubMed] [Google Scholar]
- Oelrichs R. B., Reid H. H., Bernard O., Ziemiecki A., Wilks A. F. NYK/FLK-1: a putative receptor protein tyrosine kinase isolated from E10 embryonic neuroepithelium is expressed in endothelial cells of the developing embryo. Oncogene. 1993 Jan;8(1):11–18. [PubMed] [Google Scholar]
- Pajusola K., Aprelikova O., Korhonen J., Kaipainen A., Pertovaara L., Alitalo R., Alitalo K. FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines. Cancer Res. 1992 Oct 15;52(20):5738–5743. [PubMed] [Google Scholar]
- Plate K. H., Breier G., Weich H. A., Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 1992 Oct 29;359(6398):845–848. doi: 10.1038/359845a0. [DOI] [PubMed] [Google Scholar]
- Risau W., Sariola H., Zerwes H. G., Sasse J., Ekblom P., Kemler R., Doetschman T. Vasculogenesis and angiogenesis in embryonic-stem-cell-derived embryoid bodies. Development. 1988 Mar;102(3):471–478. doi: 10.1242/dev.102.3.471. [DOI] [PubMed] [Google Scholar]
- Sarzani R., Arnaldi G., De Pirro R., Moretti P., Schiaffino S., Rappelli A. A novel endothelial tyrosine kinase cDNA homologous to platelet-derived growth factor receptor cDNA. Biochem Biophys Res Commun. 1992 Jul 31;186(2):706–714. doi: 10.1016/0006-291x(92)90804-t. [DOI] [PubMed] [Google Scholar]
- Senger D. R., Galli S. J., Dvorak A. M., Perruzzi C. A., Harvey V. S., Dvorak H. F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983 Feb 25;219(4587):983–985. doi: 10.1126/science.6823562. [DOI] [PubMed] [Google Scholar]
- 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]
- Shweiki D., Itin A., Soffer D., Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992 Oct 29;359(6398):843–845. doi: 10.1038/359843a0. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Thurlbeck W. M. Postnatal growth and development of the lung. Am Rev Respir Dis. 1975 Jun;111(6):803–844. doi: 10.1164/arrd.1975.111.6.803. [DOI] [PubMed] [Google Scholar]
- Vane J. R., Anggård E. E., Botting R. M. Regulatory functions of the vascular endothelium. N Engl J Med. 1990 Jul 5;323(1):27–36. doi: 10.1056/NEJM199007053230106. [DOI] [PubMed] [Google Scholar]
- Warrington J. A., Bailey S. K., Armstrong E., Aprelikova O., Alitalo K., Dolganov G. M., Wilcox A. S., Sikela J. M., Wolfe S. F., Lovett M. A radiation hybrid map of 18 growth factor, growth factor receptor, hormone receptor, or neurotransmitter receptor genes on the distal region of the long arm of chromosome 5. Genomics. 1992 Jul;13(3):803–808. doi: 10.1016/0888-7543(92)90156-m. [DOI] [PubMed] [Google Scholar]
- 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]
- Wilkinson D. G., Bailes J. A., McMahon A. P. Expression of the proto-oncogene int-1 is restricted to specific neural cells in the developing mouse embryo. Cell. 1987 Jul 3;50(1):79–88. doi: 10.1016/0092-8674(87)90664-7. [DOI] [PubMed] [Google Scholar]
- 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]