Urotensin II-induced signaling involved in proliferation of vascular smooth muscle cells

Myriam Iglewski, Stephen R Grant
Department of Integrative Physiology, University of North Texas Health Science Center, Fort Worth, Texas, USA

Abstract: 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 (Ca²⁺) in vascular smooth muscle cells. Ca²⁺ influx leads to the activation of Ca²⁺-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 Ca²⁺/calmodulin-dependent kinases leading to cellular proliferation. Exposure of Pac1 cultures to urotensin II increased intracellular Ca²⁺, subsequently activating Ca²⁺/calmodulin-dependent kinase kinase (CaMKK), and Ca²⁺/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 ³H-thymidine uptake. The urotensin II-induced increase in 3H-thymidine incorporation was inhibited by a CaMKK inhibitor. Taken together, our results demonstrate that urotensin II stimulation of smooth muscle cells leads to a Ca²⁺/calmodulin-dependent kinase-mediated increase in cellular proliferation.

Keywords: urotensin II receptor, CaMKI, hypertrophy, CaMKK, protein kinase D