Urotensin II-induced signaling involved in proliferation of vascular smooth muscle cells.
The urotensin II receptor, bound by the ligand urotensin II, generates second messengers, ie, inositol triphosphate and diacylglycerol, which stimulate the subsequent release of calcium (Ca(2+)) in vascular smooth muscle cells. Ca(2+) influx leads to the activation of Ca(2+)-dependent kinases (CaMK) via calmodulin binding, resulting in cellular proliferation. We hypothesize that urotensin II signaling in pulmonary arterial vascular smooth muscle cells (Pac1) and primary aortic vascular smooth muscle cells (PAVSMC) results in phosphorylation of Ca(2+)/calmodulin-dependent kinases leading to cellular proliferation. Exposure of Pac1 cultures to urotensin II increased intracellular Ca(2+), subsequently activating Ca(2+)/calmodulin-dependent kinase kinase (CaMKK), and Ca(2+)/calmodulin-dependent kinase Type I (CaMKI), extracellular signal-regulated kinase (ERK 1/2), and protein kinase D. Treatment of Pac1 and PAVSMC with urotensin II increased proliferation as measured by (3)H-thymidine uptake. The urotensin II-induced increase in (3)H-thymidine incorporation was inhibited by a CaMKK inhibitor. Taken together, our results demonstrate that urotensin II stimulation of smooth muscle cells leads to a Ca(2+)/calmodulin-dependent kinase-mediated increase in cellular proliferation.
Iglewski
Myriam
M
Department of Integrative Physiology, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA.
Grant
Stephen R
SR
D000818:Animals; D001011:Aorta / Q000502:physiology; D015153:Blotting, Western; D020013:Calcium Signaling / Q000502:physiology; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000378:metabolism; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000254:growth & development* / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011651:Pulmonary Artery / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014579:Urotensins / Q000502:physiology*
D043562:Receptors, G-Protein-Coupled; D014579:Urotensins; C473142:Uts2r protein, rat; C029677:urotensin II; C089212:protein kinase D; D011493:Protein Kinase C; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D048049:Extracellular Signal-Regulated MAP Kinases