title: Adrenomedullin promotes proliferation and migration of cultured endothelial cells.
abstract: Adrenomedullin (AM) is a vasoactive hormone which exerts its action through cyclic adenosine monophosphate(cAMP) /cAMP-dependent protein kinase (PKA) cascade and intracellular Ca2+ mobilization. Recently, evidence has accumulated that AM plays a critical role in the regulation of vascular tone, remodeling and morphogenesis. And although numerous reports have examined the action of AM on cultured vascular cells, the results have not been consistent and have depended on the experimental conditions used. Accordingly, the purpose of this study was to clarify the effect of AM on the proliferation and migration of cultured endothelial cells. Our results revealed that AM promoted the growth and migration of endothelial cells (ECs). AM significantly promoted the proliferation of human umbilical vein endothelial cells (HUVECs) (56.0 +/- 8.7% over the controls at 10(-9) mol/l) and this stimulative effect was inhibited by two AM antagonists, AM(22-52) and calcitonin gene-related peptide (CGRP) (8-37). The number of HUVECs migrated to the lower surface of the transwell apparatus was also increased dose-dependently in the AM group (30.4 +/- 4.2% over the controls at 10(-7) mol/l), and this increase was suppressed by the two AM antagonists and by two PKA antagonists, adenosine 3'5'-cyclic monophosphorothioate Rp-isomer and myristoylated protein kinase A inhibitor amide 14-22. The promoting action of AM on endothelial migration was also suppressed by LY294002, an inhibitor for phosphatidylinositol 3-kinase, but not by N(G)-nitro-L-arginine-methyl ester (L-NAME), an antagonist for nitric oxide synthase (NOS). These results indicate that AM promotes proliferation and migration of ECs via a cAMP/PKA dependent pathway and lend support to the idea that AM exerts beneficial effects on vascular regeneration and might be used as a novel therapeutic strategy for patients with vascular disease.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Miyashita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
authors.forename: Naoki
authors.initials: N
authors.lastname: Sawada
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Fukunaga
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Sone
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yamahara
authors.forename: Takami
authors.initials: T
authors.lastname: Yurugi
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D053607:Adrenomedullin; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018919:Neovascularization, Physiologic / Q000502:physiology; D010455:Peptides / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D010455:Peptides; D014665:Vasodilator Agents; D053607:Adrenomedullin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases