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J Biol Chem, Vol. 273, Issue 8, 4400-4405, February 20, 1998

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

Burak M. ArkonacDagger , Lauren C. FosterDagger , Nicholas E. S. SibingaDagger §, Cam PattersonDagger , Kaihua LaiDagger , Jer-Chia Tsai**, Mu-En LeeDagger §, Mark A. PerrellaDagger §Dagger Dagger , and Edgar HaberDagger §

From the Dagger  Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, Massachusetts 02115, the ** Department of Medicine, Kaohsiung Medical College, Kaohsiung, Taiwan, Republic of China, the § Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, and the  Cardiovascular and Dagger Dagger  Pulmonary Divisions, Brigham and Women's Hospital, Boston, Massachusetts 02115

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-beta 1 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.

Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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