title: Mechanical stretch augments insulin-induced vascular smooth muscle cell proliferation by insulin-like growth factor-1 receptor.
abstract: Insulin resistance and hypertension have been implicated in the pathogenesis of cardiovascular disease; however, little is known about the roles of insulin and mechanical force in vascular smooth muscle cell (VSMC) remodeling. We investigated the contribution of mechanical stretch to insulin-induced VSMC proliferation. Thymidine incorporation was stimulated by insulin in stretched VSMCs, but not in un-stretched VSMCs. Insulin increased 2-deoxy-glucose incorporation in both stretched and un-stretched VSMCs. Mechanical stretch augmented insulin-induced extracellular signal-regulated kinase (ERK) and Akt phosphorylation. Inhibitors of epidermal growth factor (EGF) receptor tyrosine kinase and Src attenuated insulin-induced ERK and Akt phosphorylation, as well as thymidine incorporation, whereas 2-deoxy-glucose incorporation was not affected by these inhibitors. Moreover, stretch augmented insulin-like growth factor (IGF)-1 receptor expression, although it did not alter the expression of insulin receptor and insulin receptor substrate-1. Insulin-induced ERK and Akt activation, and thymidine incorporation were inhibited by siRNA for the IGF-1 receptor. Mechanical stretch augments insulin-induced VSMC proliferation via upregulation of IGF-1 receptor, and downstream Src/EGF receptor-mediated ERK and Akt activation. Similar to in vitro experiment, IGF-1 receptor expression was also augmented in hypertensive rats. These results provide a basis for clarifying the molecular mechanisms of vascular remodeling in hypertensive patients with hyperinsulinemia.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hitomi
authors.forename: Naohisa
authors.initials: N
authors.lastname: Hosomi
authors.forename: Bai
authors.initials: B
authors.lastname: Lei
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakano
authors.forename: Kazushi
authors.initials: K
authors.lastname: Deguchi
authors.forename: Hirohito
authors.initials: H
authors.lastname: Mori
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masaki
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.forename: Kathy K
authors.initials: KK
authors.lastname: Griendling
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D066246:ErbB Receptors / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013314:Stress, Mechanical
chemical_list: D007328:Insulin; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I; D004247:DNA; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005947:Glucose