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Identification of an angiogenic mitogen selective for endocrine gland endothelium

Nature volume 412, pages 877–884 (2001)Cite this article

Abstract

The known endothelial mitogens stimulate growth of vascular endothelial cells without regard to their tissue of origin. Here we report a growth factor that is expressed largely in one type of tissue and acts selectively on one type of endothelium. This molecule, called endocrine-gland-derived vascular endothelial growth factor (EG-VEGF), induced proliferation, migration and fenestration (the formation of membrane discontinuities) in capillary endothelial cells derived from endocrine glands. However, EG-VEGF had little or no effect on a variety of other endothelial and non-endothelial cell types tested. Similar to VEGF, EG-VEGF possesses a HIF-1 binding site, and its expression is induced by hypoxia. Both EG-VEGF and VEGF resulted in extensive angiogenesis and cyst formation when delivered in the ovary. However, unlike VEGF, EG-VEGF failed to promote angiogenesis in the cornea or skeletal muscle. Expression of human EG-VEGF messenger RNA is restricted to the steroidogenic glands, ovary, testis, adrenal and placenta and is often complementary to the expression of VEGF, suggesting that these molecules function in a coordinated manner. EG-VEGF is an example of a class of highly specific mitogens that act to regulate proliferation and differentiation of the vascular endothelium in a tissue-specific manner.

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Figure 1: EG-VEGF cDNA and amino-acid sequences and alignments with homologous proteins.
Figure 2: EG-VEGF is a mitogen, chemoattractant, and inducer of fenestration for specific endothelial cells.
Figure 3: EG-VEGF expression is hypoxia inducible.
Figure 4: Northern blot analyses of human RNA samples from different tissues with an EG-VEGF specific probe.
Figure 5: Expression of EG-VEGF mRNA in testis and ovary.
Figure 6: Selectivity of the in vivo angiogenic effects of EG-VEGF.

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Acknowledgements

We thank the oligonucleotide-synthesis, DNA-sequencing and protein-purification groups; D. Tran and G. Bennett for protein iodination; P. Schow for cell sorting; M. van Hoy for necropsy; and R. Taylor and P. Tobin for histology. We also thank H. Chen for initial observations and J. Singh and L. Yu for cell culture and transfections.

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Authors and Affiliations

  1. Department of Molecular Oncology,

    Jennifer LeCouter, Joe Kowalski, Leo DeGuzman & Napoleone Ferrara

  2. Department of Molecular Biology, Genentech Inc., South San Francisco, 94080, California, USA

    Jessica Foster, Zemin Zhang & Austin Gurney

  3. Department of Protein Chemistry, Genentech Inc., South San Francisco, 94080, California, USA

    Phil Hass

  4. Department of Pathology, Genentech Inc., South San Francisco, 94080, California, USA

    Lisa Dillard-Telm, Gretchen Frantz, Franklin Peale & Kenneth J. Hillan

  5. Department of Toxicology/Pathology, Genentech Inc., South San Francisco, 94080, California, USA

    Linda Rangell & Gilbert-Andre Keller

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LeCouter, J., Kowalski, J., Foster, J. et al. Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature 412, 877–884 (2001). https://doi.org/10.1038/35091000

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