help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Iwasaki, H.
Right arrow Articles by Hirata, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Iwasaki, H.
Right arrow Articles by Hirata, Y.
Endocrinology Vol. 139, No. 8 3432-3441
Copyright © 1998 by The Endocrine Society

ARTICLES

Adrenomedullin as a Novel Growth-Promoting Factor for Cultured Vascular Smooth Muscle Cells: Role of Tyrosine Kinase-Mediated Mitogen-Activated Protein Kinase Activation1

Hiroaki Iwasaki, Satoru Eguchi, Masayoshi Shichiri, Fumiaki Marumo and Yukio Hirata

Endocrine-Hypertension Division, Second Department of Internal Medicine, Tokyo Medical and Dental University, 1–5-45 Yushima, Bunkyo-ku, Tokyo 113, Japan

Address all correspondence and requests for reprints to: Dr. Yukio Hirata, Second Department of Internal Medicine, Tokyo Medical and Dental University, 1–5-45 Yushima, Bunkyo-ku, Tokyo 113, Japan.

To examine whether adrenomedullin (AM), a novel vasodilator peptide, acts as a growth modulator in the vasculature, the effects of AM on protein tyrosine phosphorylation, mitogen-activated protein kinase (MAPK) activation, protooncogene expression, DNA synthesis, and cell proliferation were studied in cultured rat vascular smooth muscle cells (VSMC). AM and calcitonin gene-related peptide (CGRP), although weaker than AM, stimulated DNA synthesis and cell proliferation of quiescent VSMC, whose effects were inhibited by a CGRP receptor antagonist, CGRP-(8–37). AM induced a rapid increase in MAPK activity, followed by the expression of the immediate early protooncogene c-fos. AM-induced MAPK activation and cell proliferation were completely blocked by protein tyrosine kinase inhibitors (genistein and ST638). Moreover, AM rapidly induced tyrosine phosphorylation of several proteins (~120, ~90, and ~50 kDa) and transiently increased association of a tyrosine-phosphorylated protein (~120 kDa) and Shc with the glutathione-S-transferase-Grb2 fusion protein. A MAPK kinase inhibitor (PD98059) also reduced the AM-induced MAPK activation, c-fos messenger RNA expression, and cell proliferation. Although AM has been shown to induce vasodilation through cAMP production in VSMC, a cAMP antagonist (Rp-cAMP-thionate) and a protein kinase A inhibitor (KT5720) failed to block AM-induced MAPK activation and DNA synthesis. Moreover, 8-bromo-cAMP and forskolin did not affect the MAPK activity. AM had no effect on either the intracellular Ca2+ concentration or inositol 1,4,5-trisphosphate formation. In addition, a protein kinase C inhibitor (GF109203X) did not inhibit the AM-induced MAPK activation. These data suggest that in addition to its vasodilatory effect through the cAMP-dependent pathway, AM exerts its mitogenic activity via protein tyrosine kinase-mediated MAPK activation in quiescent rat VSMC.




This article has been cited by other articles:


Home page
 Mol. Cell. Biol.Home page
R. T. Dackor, K. Fritz-Six, W. P. Dunworth, C. L. Gibbons, O. Smithies, and K. M. Caron
Hydrops fetalis, cardiovascular defects, and embryonic lethality in mice lacking the calcitonin receptor-like receptor gene.
Mol. Cell. Biol., April 1, 2006; 26(7): 2511 - 2518.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J.-Y. Kim, J.-H. Yim, J.-H. Cho, J.-H. Kim, J.-H. Ko, S.-M. Kim, S. Park, and J.-H. Park
Adrenomedullin Regulates Cellular Glutathione Content via Modulation of {gamma}-Glutamate-Cysteine Ligase Catalytic Subunit Expression
Endocrinology, March 1, 2006; 147(3): 1357 - 1364.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
J. Kato, T. Tsuruda, T. Kita, K. Kitamura, and T. Eto
Adrenomedullin: A Protective Factor for Blood Vessels
Arterioscler. Thromb. Vasc. Biol., December 1, 2005; 25(12): 2480 - 2487.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
N. Fukai, T. Yoshimoto, T. Sugiyama, N. Ozawa, R. Sato, M. Shichiri, and Y. Hirata
Concomitant expression of adrenomedullin and its receptor components in rat adipose tissues
Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E56 - E62.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
S. Iimuro, T. Shindo, N. Moriyama, T. Amaki, P. Niu, N. Takeda, H. Iwata, Y. Zhang, A. Ebihara, and R. Nagai
Angiogenic Effects of Adrenomedullin in Ischemia and Tumor Growth
Circ. Res., August 20, 2004; 95(4): 415 - 423.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
T. Yoshimoto, N. Fukai, R. Sato, T. Sugiyama, N. Ozawa, M. Shichiri, and Y. Hirata
Antioxidant Effect of Adrenomedullin on Angiotensin II-Induced Reactive Oxygen Species Generation in Vascular Smooth Muscle Cells
Endocrinology, July 1, 2004; 145(7): 3331 - 3337.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
M. Matsushita, M. Shichiri, N. Fukai, N. Ozawa, T. Yoshimoto, N. Takasu, and Y. Hirata
Urotensin II is an Autocrine/Paracrine Growth Factor for the Porcine Renal Epithelial Cell Line, LLCPK1
Endocrinology, May 1, 2003; 144(5): 1825 - 1831.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
N. Fukai, M. Shichiri, N. Ozawa, M. Matsushita, and Y. Hirata
Coexpression of Calcitonin Receptor-Like Receptor and Receptor Activity-Modifying Protein 2 or 3 Mediates the Antimigratory Effect of Adrenomedullin
Endocrinology, February 1, 2003; 144(2): 447 - 453.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
A. Martinez, M. Vos, L. Guedez, G. Kaur, Z. Chen, M. Garayoa, R. Pio, T. Moody, W. G. Stetler-Stevenson, H. K. Kleinman, et al.
The Effects of Adrenomedullin Overexpression in Breast Tumor Cells
J Natl Cancer Inst, August 21, 2002; 94(16): 1226 - 1237.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
T. Shindo, Y. Kurihara, H. Nishimatsu, N. Moriyama, M. Kakoki, Y. Wang, Y. Imai, A. Ebihara, T. Kuwaki, K.-H. Ju, et al.
Vascular Abnormalities and Elevated Blood Pressure in Mice Lacking Adrenomedullin Gene
Circulation, October 16, 2001; 104(16): 1964 - 1971.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
S. Dunzendorfer, A. Kaser, C. Meierhofer, H. Tilg, and C. J. Wiedermann
Cutting Edge: Peripheral Neuropeptides Attract Immature and Arrest Mature Blood-Derived Dendritic Cells
J. Immunol., February 15, 2001; 166(4): 2167 - 2172.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
H. Iwasaki, M. Shichiri, F. Marumo, and Y. Hirata
Adrenomedullin Stimulates Proline-Rich Tyrosine Kinase 2 in Vascular Smooth Muscle Cells
Endocrinology, February 1, 2001; 142(2): 564 - 572.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
P. D. Upton, J. Wharton, H. Coppock, N. Davie, X. Yang, M. H. Yacoub, M. A. Ghatei, J. M. Polak, S. R. Bloom, D. M. Smith, et al.
Adrenomedullin Expression and Growth Inhibitory Effects in Distinct Pulmonary Artery Smooth Muscle Cell Subpopulations
Am. J. Respir. Cell Mol. Biol., February 1, 2001; 24(2): 170 - 178.
[Abstract] [Full Text]

Home page
 EndocrinologyHome page
P. G. Andreis, A. Markowska, H. C. Champion, G. Mazzocchi, L. K. Malendowicz, and G. G. Nussdorfer
Adrenomedullin Enhances Cell Proliferation and Deoxyribonucleic Acid Synthesis in Rat Adrenal Zona Glomerulosa: Receptor Subtype Involved and Signaling Mechanism
Endocrinology, June 1, 2000; 141(6): 2098 - 2104.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
J. P. Hinson, S. Kapas, and D. M. Smith
Adrenomedullin, a Multifunctional Regulatory Peptide
Endocr. Rev., April 1, 2000; 21(2): 138 - 167.
[Abstract] [Full Text]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
H. Iwasaki, S. Eguchi, H. Ueno, F. Marumo, and Y. Hirata
Mechanical stretch stimulates growth of vascular smooth muscle cells via epidermal growth factor receptor
Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H521 - H529.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
K. Shimizu, H. Tanaka, M. Sunamori, F. Marumo, and M. Shichiri
Adrenomedullin Receptor Antagonism by Calcitonin Gene-Related Peptide(8-37) Inhibits Carotid Artery Neointimal Hyperplasia After Balloon Injury
Circ. Res., December 3, 1999; 85(12): 1199 - 1205.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
H. Iwasaki, S. Eguchi, H. Ueno, F. Marumo, and Y. Hirata
Endothelin-Mediated Vascular Growth Requires p42/p44 Mitogen-Activated Protein Kinase and p70 S6 Kinase Cascades via Transactivation of Epidermal Growth Factor Receptor
Endocrinology, October 1, 1999; 140(10): 4659 - 4668.
[Abstract] [Full Text]

Home page
 Mol. Endocrinol.Home page
M. Shichiri, H. Kato, M. Doi, F. Marumo, and Y. Hirata
Induction of Max by Adrenomedullin and Calcitonin Gene-Related Peptide Antagonizes Endothelial Apoptosis
Mol. Endocrinol., August 1, 1999; 13(8): 1353 - 1363.
[Abstract] [Full Text]

Home page
 Circ. Res.Home page
H. Nishimatsu, E. Suzuki, D. Nagata, N. Moriyama, H. Satonaka, K. Walsh, M. Sata, K. Kangawa, H. Matsuo, A. Goto, et al.
Adrenomedullin Induces Endothelium-Dependent Vasorelaxation via the Phosphatidylinositol 3-Kinase/Akt-Dependent Pathway in Rat Aorta
Circ. Res., July 6, 2001; 89(1): 63 - 70.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 1998 by The Endocrine Society