title: Adrenomedullin is an autocrine/paracrine growth factor for rat vascular smooth muscle cells.
abstract: Adrenomedullin is a potent vasodilator peptide secreted by vascular endothelial and smooth muscle cells. Adrenomedullin stimulates the proliferation of quiescent rat vascular smooth muscle cells (VSMCs) via p42/p44 ERK/MAP kinase activation. Recently, receptor-activity-modifying proteins (RAMPs) have been shown to transport calcitonin-receptor-like-receptor (CRLR) to the cell surface to present either as CGRP receptor or adrenomedullin receptor. We investigated whether adrenomedullin acts as an autocrine/paracrine growth factor for cultured rat VSMCs and whether coexpressions of RAMP isoform and CRLR may mediate p42/p44 ERK/MAP kinase activation by adrenomedullin. Adrenomedullin dose-dependently stimulated the proliferation of quiescent rat VSMCs, and this effect was inhibited by an adrenomedullin receptor antagonist, a MAP kinase kinase inhibitor and phosphatidylinositol 3-kinase inhibitors. Addition of either CGRP(8-37) or anti-adrenomedullin antibody to exponentially growing rat VSMCs inhibited the serum-induced cell proliferation, suggesting its role as an autocrine/paracrine growth factor. Cotransfection of RAMP2 or RAMP3 with CRLR into rat VSMCs potentiated activation of cAMP activity, but not of p42/p44 ERK/MAP kinase activity in response to adrenomedullin. Our results suggest that adrenomedullin is an autocrine/paracrine growth factor for rat VSMCs via p42/p44 ERK/MAP kinase and phosphatidylinositol 3-kinase pathways and that it is not mediated by human RAMP-CRLR receptors.
authors.affiliation: Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, 1-5-45, Yushima, Tokyo 113-8519, Bunkyo, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Shichiri
authors.forename: Nozomi
authors.initials: N
authors.lastname: Fukai
authors.forename: Naoko
authors.initials: N
authors.lastname: Ozawa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hirata
mesh_terms: D053607:Adrenomedullin; D000818:Animals; D019898:Autocrine Communication; D058286:Calcitonin Receptor-Like Protein; D002452:Cell Count; D002454:Cell Differentiation; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D006133:Growth Substances / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019899:Paracrine Communication; D010455:Peptides / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin / Q000378:metabolism
chemical_list: C545578:CALCRL protein, human; D058286:Calcitonin Receptor-Like Protein; C545580:Calcrl protein, rat; D006133:Growth Substances; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010455:Peptides; C545503:RAMP2 protein, human; C545504:RAMP3 protein, human; C545509:Ramp2 protein, rat; C545510:Ramp3 protein, rat; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin; D053607:Adrenomedullin; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases