This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Reynolds, C. M. Articles by Motley, E. D. Search for Related Content PubMed PubMed Citation Articles by Reynolds, C. M. Articles by Motley, E. D. Related Collections Smooth muscle proliferation and differentiation Mechanism of atherosclerosis/growth factors

(Hypertension. 2002;39:525.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Signaling Mechanisms of Heparin-Binding Epidermal Growth Factor-Like Growth Factor in Vascular Smooth Muscle Cells

Cherilynn M. Reynolds; Satoru Eguchi; Gerald D. Frank; Evangeline D. Motley

From the Department of Anatomy and Physiology, Meharry Medical College (C.M.R., E.D.M.), Nashville, Tenn; and the Department of Biochemistry, Vanderbilt University School of Medicine (S.E., G.D.F.), Nashville, Tenn.

Correspondence to Evangeline D. Motley, PhD, Department of Anatomy and Physiology, Meharry Medical College, 1005 D.B. Todd Boulevard, Nashville, TN 37208. E-mail emotley{at}mmc.edu

A host of growth factors have been implicated in vascular pathologies; one such factor is heparin-binding epidermal growth factor-like growth factor (HB-EGF). Although HB-EGF has been shown to stimulate mitogenesis and chemotaxis of vascular smooth muscle cells (VSMC), its signaling mechanism remains undefined. In this study, we examined possible signal transduction pathways by which HB-EGF leads to mitogenesis in cultured rat VSMC. HB-EGF induced phosphorylation of the EGF receptor (EGFR) with maximum phosphorylation at 0.5 to 1 minute, whereas erbB4, the other receptor to which HB-EGF binds, was not activated on HB-EGF stimulation. HB-EGF induced a time- and concentration-dependent phosphorylation of mitogen-activated protein kinase (MAPK; p42/44 MAPK, extracellular signal-regulating kinase [ERK] 1/2). It also activated Akt and p70S6 kinase (p70S6K) but not p38 MAPK. HB-EGF-induced phosphorylation of these kinases was blocked by the EGFR kinase inhibitor AG1478. To investigate signaling molecules involved in HB-EGF-induced DNA synthesis, we pretreated VSMC with the specific ERK kinase mitogen-activated kinase (MEK) inhibitor PD98059 and the phosphatidylinositol 3-kinase inhibitor LY294002. These inhibitors significantly blocked HB-EGF-induced DNA synthesis. PD98059 inhibited HB-EGF-induced ERK activation, whereas it had no effect on Akt activation by HB-EGF. By contrast, LY294002 inhibited HB-EGF-induced Akt and p70S6K activation without effecting ERK activation by HB-EGF. These results demonstrate that HB-EGF-induced mitogenesis requires both ERK and phosphatidylinositol 3-kinase (Akt and p70S6K) pathways activated through EGFR, thereby providing a new mechanistic insight by which HB-EGF contributes to vascular remodeling.

Key Words: atherosclerosis • epidermal growth factor • heparin • muscle, smooth, vascular • signal transduction

This article has been cited by other articles:

				Y. Fukatsu, T. Noguchi, T. Hosooka, T. Ogura, K. Kotani, T. Abe, T. Shibakusa, K. Inoue, M. Sakai, K. Tobimatsu, et al. Muscle-Specific Overexpression of Heparin-Binding Epidermal Growth Factor-Like Growth Factor Increases Peripheral Glucose Disposal and Insulin Sensitivity Endocrinology, June 1, 2009; 150(6): 2683 - 2691. [Abstract] [Full Text] [PDF]

				D. Chansel, M. Ciroldi, S. Vandermeersch, L. F Jackson, A.-M. Gomez, D. Henrion, D. C. Lee, T. M. Coffman, S. Richard, J.-C. Dussaule, et al. Heparin binding EGF is necessary for vasospastic response to endothelin FASEB J, September 1, 2006; 20(11): 1936 - 1938. [Abstract] [Full Text] [PDF]

				J. Wang, N. Ohara, S. Takekida, Q. Xu, and T. Maruo Comparative effects of heparin-binding epidermal growth factor-like growth factor on the growth of cultured human uterine leiomyoma cells and myometrial cells Hum. Reprod., June 1, 2005; 20(6): 1456 - 1465. [Abstract] [Full Text] [PDF]

				M. Mifune, H. Ohtsu, H. Suzuki, G. D. Frank, T. Inagami, H. Utsunomiya, P. J. Dempsey, and S. Eguchi Signal transduction of betacellulin in growth and migration of vascular smooth muscle cells Am J Physiol Cell Physiol, September 1, 2004; 287(3): C807 - C813. [Abstract] [Full Text] [PDF]

				B. H. Shah, A. Yesilkaya, J. A. Olivares-Reyes, H.-D. Chen, L. Hunyady, and K. J. Catt Differential Pathways of Angiotensin II-Induced Extracellularly Regulated Kinase 1/2 Phosphorylation in Specific Cell Types: Role of Heparin-Binding Epidermal Growth Factor Mol. Endocrinol., August 1, 2004; 18(8): 2035 - 2048. [Abstract] [Full Text] [PDF]

				B. H. Shah, M. P. Farshori, and K. J. Catt Neuropeptide-induced Transactivation of a Neuronal Epidermal Growth Factor Receptor Is Mediated by Metalloprotease-dependent Formation of Heparin-binding Epidermal Growth Factor J. Biol. Chem., January 2, 2004; 279(1): 414 - 420. [Abstract] [Full Text] [PDF]

				J. Lai, J. Chien, J. Staub, R. Avula, E. L. Greene, T. A. Matthews, D. I. Smith, S. H. Kaufmann, L. R. Roberts**, and V. Shridhar** Loss of HSulf-1 Up-regulates Heparin-binding Growth Factor Signaling in Cancer J. Biol. Chem., June 13, 2003; 278(25): 23107 - 23117. [Abstract] [Full Text] [PDF]