Identification of an angiogenic mitogen selective for endocrine gland endothelium

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.

[1]  R. L. Hall,et al.  Preclinical Safety Evaluation of rhuMAbVEGF, an Antiangiogenic Humanized Monoclonal Antibody , 1999, Toxicologic pathology.

[2]  J. Boisbouvier,et al.  A structural homologue of colipase in black mamba venom revealed by NMR floating disulphide bridge analysis. , 1998, Journal of molecular biology.

[3]  E. Oldfield,et al.  Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues. , 1993, The American journal of physiology.

[4]  E. Shakhnovich,et al.  Protein folding: Think globally, (inter)act locally , 1998, Current Biology.

[5]  G. Semenza.  HIF-1: mediator of physiological and pathophysiological responses to hypoxia. , 2000, Journal of applied physiology.

[6]  Kenneth J. Hillan,et al.  Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene , 1996, Nature.

[7]  D. L. Bassett.  The changes in the vascular pattern of the ovary of the albino rat during the estrous cycle , 1943 .

[8]  D. Goeddel,et al.  Vascular endothelial growth factor is a secreted angiogenic mitogen. , 1989, Science.

[9]  H. Phillips,et al.  Vascular endothelial growth factor messenger ribonucleic acid expression in the primate ovary. , 1992, Endocrinology.

[10]  C. Wechselberger,et al.  The mammalian homologues of frog Bv8 are mainly expressed in spermatocytes , 1999, FEBS letters.

[11]  Y. Dor,et al.  Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis. , 2001, American journal of physiology. Cell physiology.

[12]  D. J. Strydom,et al.  Snake venom. The amino acid sequence of protein A from Dendroaspis polylepis polylepis (black mamba) venom. , 1980, Hoppe-Seyler's Zeitschrift fur physiologische Chemie.

[13]  M. Wiley,et al.  Developing nervous tissue induces formation of blood-brain barrier characteristics in invading endothelial cells: a study using quail--chick transplantation chimeras. , 1981, Developmental biology.

[14]  M. Lazdunski,et al.  MIT1, a black mamba toxin with a new and highly potent activity on intestinal contraction , 1999, FEBS letters.

[15]  N. Simionescu,et al.  Structural aspects of the permeability of the microvascular endothelium. , 1979, Acta physiologica Scandinavica. Supplementum.

[16]  Kenneth J. Hillan,et al.  Vascular endothelial growth factor is essential for corpus luteum angiogenesis , 1998, Nature Medicine.

[17]  Dian Feng,et al.  Heterogeneity of the Angiogenic Response Induced in Different Normal Adult Tissues by Vascular Permeability Factor/Vascular Endothelial Growth Factor , 2000, Laboratory Investigation.

[18]  M Aguet,et al.  VEGF is required for growth and survival in neonatal mice. , 1999, Development.

[19]  J. Folkman,et al.  Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathways. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[20]  B. Zetter,et al.  Migration of capillary endothelial cells is stimulated by tumour-derived factors , 1980, Nature.

[21]  Stanley J. Wiegand,et al.  Vascular-specific growth factors and blood vessel formation , 2000, Nature.

[22]  L. Aiello,et al.  Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. , 1994, The New England journal of medicine.

[23]  H. Phillips,et al.  Vascular endothelial growth factor is expressed in rat corpus luteum. , 1990, Endocrinology.

[24]  N. Ferrara,et al.  Analysis of Biological Effects and Signaling Properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2) , 2001, The Journal of Biological Chemistry.

[25]  D. Gospodarowicz,et al.  Comparison of the ability of basement membranes produced by corneal endothelial and mouse-derived Endodermal PF-HR-9 cells to support the proliferation and differentiation of bovine kidney tubule epithelial cells in vitro , 1984, The Journal of cell biology.

[26]  C. Niehrs,et al.  Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction , 1998, Nature.

[27]  S. Soker,et al.  Neuropilin-1 Mediates Collapsin-1/Semaphorin III Inhibition of Endothelial Cell Motility , 1999, The Journal of cell biology.

[28]  R K Jain,et al.  Quantitation and physiological characterization of angiogenic vessels in mice: effect of basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor, and host microenvironment. , 1996, The American journal of pathology.

[29]  Napoleone Ferrara,et al.  Clinical applications of angiogenic growth factors and their inhibitors , 1999, Nature Medicine.

[30]  P. Carmeliet.  Mechanisms of angiogenesis and arteriogenesis , 2000, Nature Medicine.

[31]  J. Folkman.  Angiogenesis in cancer, vascular, rheumatoid and other disease , 1995, Nature Medicine.

[32]  D. Melton,et al.  Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. , 1984, Nucleic acids research.

[33]  G. Breier,et al.  Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. , 1992, Development.

[34]  K. Robison,et al.  Functional and structural diversity of the human Dickkopf gene family. , 1999, Gene.

[35]  A. Bergh,et al.  Leydig cells secrete factors which increase vascular permeability and endothelial cell proliferation. , 1996, International journal of andrology.

[36]  Napoleone Ferrara,et al.  VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation , 1999, Nature Medicine.

[37]  Bing Li,et al.  Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo , 1993, Nature.

[38]  G. Palade,et al.  Neovasculature induced by vascular endothelial growth factor is fenestrated. , 1997, Cancer research.

[39]  H. Tilbeurgh,et al.  Structure of the pancreatic lipase–procolipase complex , 1992, Nature.

[40]  H. Phillips,et al.  Widespread expression of BDNF but not NT3 by target areas of basal forebrain cholinergic neurons. , 1990, Science.

[41]  M. Klagsbrun.  Mediators of angiogenesis: the biological significance of basic fibroblast growth factor (bFGF)-heparin and heparan sulfate interactions. , 1992, Seminars in cancer biology.

[42]  W. Aird,et al.  Vascular Bed–specific Expression of an Endothelial Cell Gene Is Programmed by the Tissue Microenvironment , 1997, The Journal of cell biology.

[43]  N. Ferrara.  VEGF: an update on biological and therapeutic aspects. , 2000, Current opinion in biotechnology.