title: Regulation and function of Cav3.1 T-type calcium channels in IGF-I-stimulated pulmonary artery smooth muscle cells.
abstract: Arterial smooth muscle cells enter the cell cycle and proliferate in conditions of disease and injury, leading to adverse vessel remodeling. In the pulmonary vasculature, diverse stimuli cause proliferation of pulmonary artery smooth muscle cells (PASMCs), pulmonary artery remodeling, and the clinical condition of pulmonary hypertension associated with significant health consequences. PASMC proliferation requires extracellular Ca(2+) influx that is intimately linked with intracellular Ca(2+) homeostasis. Among the primary sources of Ca(2+) influx in PASMCs is the low-voltage-activated family of T-type Ca(2+) channels; however, up to now, mechanisms for the action of T-type channels in vascular smooth muscle cell proliferation have not been addressed. The Ca(v)3.1 T-type Ca(2+) channel mRNA is upregulated in cultured PASMCs stimulated to proliferate with insulin-like growth factor-I (IGF-I), and this upregulation depends on phosphatidylinositol 3-kinase/Akt signaling. Multiple stimuli that trigger an acute rise in intracellular Ca(2+) in PASMCs, including IGF-I, also require the expression of Ca(v)3.1 Ca(2+) channels for their action. IGF-I also led to cell cycle initiation and proliferation of PASMCs, and, when expression of the Ca(v)3.1 Ca(2+) channel was knocked down by RNA interference, so were the expression and activation of cyclin D, which are necessary steps for cell cycle progression. These results confirm the importance of T-type Ca(2+) channels in proper progression of the cell cycle in PASMCs stimulated to proliferate by IGF-I and suggest that Ca(2+) entry through Ca(v)3.1 T-type channels in particular interacts with Ca(2+)-dependent steps of the mitogenic signaling cascade as a central component of vascular remodeling in disease.
authors.affiliation: Department of Medicine, Loyola Univ. Chicago, 2160 S. 1 Ave., Maywood, IL 60153, USA.
authors.forename: Florentina
authors.initials: F
authors.lastname: Pluteanu
authors.forename: Leanne L
authors.initials: LL
authors.lastname: Cribbs
mesh_terms: D000818:Animals; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology; D006984:Hypertrophy; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008934:Mitogens / Q000235:genetics / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D015398:Signal Transduction / Q000235:genetics
chemical_list: C500994:Cacna1g protein, rat; D020747:Calcium Channels, T-Type; D008934:Mitogens; D007334:Insulin-Like Growth Factor I