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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.




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