Vascular Endothelial Growth Factor Induces Heparin-binding Epidermal Growth Factor-like Growth Factor in Vascular Endothelial Cells*

Although several cytokines and growth factors have been shown to regulate vascular endothelial growth factor (VEGF) production, little is known about how VEGF may regulate growth factors that have known mitogenic and chemotactic actions on mesenchymal cells (which are involved in the maturation of the angiogenic process). We investigated the effect of VEGF on heparin-binding epidermal growth factor-like growth factor (HB-EGF) expression in human umbilical vein endothelial cells. HB-EGF mRNA was induced by 8-fold after 2 h of VEGF stimulation, and it returned to base line within 6 h. VEGF did not alter the half-life of HB-EGF mRNA (55 min). Nuclear run-on experiments showed a 4.9-fold increase in HB-EGF gene transcription within 2 h of VEGF stimulation, and Western analysis demonstrated an associated increase in cellular HB-EGF protein. We found that platelet-derived growth factor-BB (PDGF-BB) mRNA was also induced 3-fold after 5 h of VEGF stimulation, whereas neither endothelin 1 nor transforming growth factor-β1 was regulated by VEGF. Finally, conditioned medium from VEGF-stimulated endothelial cells produced an increase in DNA synthesis in vascular smooth muscle cells, and this effect was blocked by a neutralizing antibody to PDGF. The induction of HB-EGF and PDGF-BB expression in endothelial cells may represent the mechanism by which VEGF recruits mesenchymal cells to form the medial and adventitial layers of arterioles and venules during the course of angiogenesis.

[1]  B R Johansson,et al.  Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. , 1997, Science.

[2]  M. Runge,et al.  Induction of vascular endothelial growth factor in balloon-injured baboon arteries. A novel role for reactive oxygen species in atherosclerosis. , 1997, Circulation research.

[3]  Pamela F. Jones,et al.  Requisite Role of Angiopoietin-1, a Ligand for the TIE2 Receptor, during Embryonic Angiogenesis , 1996, Cell.

[4]  J. Folkman,et al.  Blood Vessel Formation: What Is Its Molecular Basis? , 1996, Cell.

[5]  S. Epstein,et al.  Comparative effects of basic fibroblast growth factor and vascular endothelial growth factor on coronary collateral development and the arterial response to injury. , 1996, Circulation.

[6]  D. Hanahan,et al.  Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis , 1996, Cell.

[7]  Lieve Moons,et al.  Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele , 1996, Nature.

[8]  V. V. van Hinsbergh,et al.  Cooperative effect of TNFalpha, bFGF, and VEGF on the formation of tubular structures of human microvascular endothelial cells in a fibrin matrix. Role of urokinase activity , 1996, The Journal of cell biology.

[9]  M. Goldberg,et al.  Post-transcriptional Regulation of Vascular Endothelial Growth Factor by Hypoxia (*) , 1996, The Journal of Biological Chemistry.

[10]  B. Keyt,et al.  Hypoxia-induced paracrine regulation of vascular endothelial growth factor receptor expression. , 1996, The Journal of clinical investigation.

[11]  G. Neufeld,et al.  Interleukin 6 Induces the Expression of Vascular Endothelial Growth Factor (*) , 1996, The Journal of Biological Chemistry.

[12]  J. Folkman.  Clinical Applications of Research on Angiogenesis , 1995 .

[13]  Yasuhiko Hayashi,et al.  Possible Participation of Autocrine and Paracrine Vascular Endothelial Growth Factors in Hypoxia-induced Proliferation of Endothelial Cells and Pericytes (*) , 1995, The Journal of Biological Chemistry.

[14]  R. Nicosia,et al.  Rat aortic smooth muscle cells become pericytes during angiogenesis in vitro. , 1995, Laboratory investigation; a journal of technical methods and pathology.

[15]  E. Haber,et al.  Cloning and Functional Analysis of the Promoter for KDR/flk-1, a Receptor for Vascular Endothelial Growth Factor(*) , 1995, The Journal of Biological Chemistry.

[16]  S. Soker,et al.  Peripheral blood T lymphocytes and lymphocytes infiltrating human cancers express vascular endothelial growth factor: a potential role for T cells in angiogenesis. , 1995, Cancer research.

[17]  M. Kuzuya,et al.  Induction of angiogenesis by smooth muscle cell‐derived factor: Possible role in neovascularization in atherosclerotic plaque , 1995, Journal of cellular physiology.

[18]  J. Rossant,et al.  Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium , 1995, Nature.

[19]  Janet Rossant,et al.  Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice , 1995, Nature.

[20]  A. Giaid,et al.  ENDOTHELIN‐1 IMMUNOREACTIVITY AND mRNA IN THE TRANSPLANTED HUMAN HEART , 1995, Transplantation.

[21]  H. Dvorak,et al.  Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. , 1995, The American journal of pathology.

[22]  S. Mandriota,et al.  Vascular Endothelial Growth Factor Increases Urokinase Receptor Expression in Vascular Endothelial Cells (*) , 1995, The Journal of Biological Chemistry.

[23]  C. Patterson,et al.  Induction of Vascular Endothelial Growth Factor Gene Expression by Interleukin-1 in Rat Aortic Smooth Muscle Cells (*) , 1995, The Journal of Biological Chemistry.

[24]  S. Yamashita,et al.  Localization of heparin-binding EGF-like growth factor in the smooth muscle cells and macrophages of human atherosclerotic plaques. , 1995, The Journal of clinical investigation.

[25]  V. Nehls,et al.  The effect of fibroblasts, vascular smooth muscle cells, and pericytes on sprout formation of endothelial cells in a fibrin gel angiogenesis system. , 1994, Microvascular research.

[26]  M. Klagsbrun,et al.  Biosynthesis and processing by phorbol ester of the cells surface-associated precursor form of heparin-binding EGF-like growth factor. , 1994, Biochemical and biophysical research communications.

[27]  S M Schwartz,et al.  Angiogenesis in human coronary atherosclerotic plaques. , 1994, The American journal of pathology.

[28]  Atsushi Namiki,et al.  Indirect Angiogenic Cytokines Upregulate VEGF and bFGF Gene Expression in Vascular Smooth Muscle Cells, Whereas Hypoxia Upregulates VEGF Expression Only , 1994 .

[29]  J. Tsai,et al.  Transforming growth factor-beta 1, but not dexamethasone, down-regulates nitric-oxide synthase mRNA after its induction by interleukin-1 beta in rat smooth muscle cells. , 1994, The Journal of biological chemistry.

[30]  M. Klagsbrun,et al.  Heparin-binding EGF-like growth factor gene is induced in the mouse uterus temporally by the blastocyst solely at the site of its apposition: a possible ligand for interaction with blastocyst EGF-receptor in implantation. , 1994, Development.

[31]  J. Winkles,et al.  Constitutive endothelin-1 overexpression promotes smooth muscle cell proliferation via an external autocrine loop. , 1994, The Journal of biological chemistry.

[32]  E. Krebs,et al.  Insulin-like growth factor-I and platelet-derived growth factor-BB induce directed migration of human arterial smooth muscle cells via signaling pathways that are distinct from those of proliferation. , 1994, The Journal of clinical investigation.

[33]  G. Neufeld,et al.  Vascular endothelial growth factor and its receptors. , 1994, Progress in growth factor research.

[34]  R. Nagai,et al.  Shear stress increases heparin-binding epidermal growth factor-like growth factor mRNA levels in human vascular endothelial cells. , 1993, Biochemical and biophysical research communications.

[35]  Shay Soker,et al.  VEGF/VPF: The angiogenesis factor found? , 1993, Current Biology.

[36]  M. Klagsbrun,et al.  Appearance of heparin-binding EGF-like growth factor in wound fluid as a response to injury. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[37]  L. Orci,et al.  Biphasic Effect of Transforming Growth Factor-β1 on in Vitro Angiogenesis , 1993 .

[38]  Sandra R. Smith,et al.  Growth factor effects on cells of the vascular wall: a survey. , 1993, Growth factors.

[39]  W. Reinhold,et al.  Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. , 1993, The Journal of clinical investigation.

[40]  T. Quertermous,et al.  Induction of heparin-binding epidermal growth factor-like growth factor mRNA by phorbol ester and angiotensin II in rat aortic smooth muscle cells. , 1992, The Journal of biological chemistry.

[41]  E. Keshet,et al.  Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis , 1992, Nature.

[42]  T. Quertermous,et al.  Tumor necrosis factor increases transcription of the heparin-binding epidermal growth factor-like growth factor gene in vascular endothelial cells. , 1992, The Journal of biological chemistry.

[43]  P. D’Amore,et al.  Capillary growth: a two-cell system. , 1992, Seminars in cancer biology.

[44]  M. Klagsbrun,et al.  Structure of heparin-binding EGF-like growth factor. Multiple forms, primary structure, and glycosylation of the mature protein. , 1992, The Journal of biological chemistry.

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

[46]  M. Klagsbrun,et al.  A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF , 1991, Science.

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

[48]  D. Connolly,et al.  Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. , 1989, The Journal of clinical investigation.

[49]  R. Eddy,et al.  Structural organization and chromosomal assignment of the gene encoding endothelin. , 1989, The Journal of biological chemistry.

[50]  P A D'Amore,et al.  Inhibition of capillary endothelial cell growth by pericytes and smooth muscle cells , 1987, The Journal of cell biology.