Abstract
Inhibition of protein tyrosine phosphatase by orthovanadate induces vasoconstriction, which is mediated by the Rho kinase-dependent inactivation of myosin light chain phosphatase (MLCP) via signaling downstream of Src-induced activation of the epidermal growth factor (EGF) receptor. The present study investigated the potential role of EGF in orthovanadate (OVA)-dependent vaso-constriction. OVA-induced aortic contraction significantly increased in the presence of EGF, and was abolished by inhibitors of Rho kinase (Y27632), extracellular signal-regulated kinase 1 and 2 (Erk1/2) (FR180204), Erk1/2 kinase (PD98059), EGF receptor (AG1478), and Src (PP2). Treatment of the rat endothelium-denuded thoracic aorta with either EGF or OVA augmented the phosphorylation of myosin phosphatase target subunit 1 (MYPT1) at Thr-853 and of the EGF receptor at Tyr-1173. The phosphorylation of MYPT1 was further increased by co-stimulation with EGF and OVA. EGF receptor phosphorylation at Tyr-845 was also increased by EGF or OVA; this effect was augmented by co-stimulation with EGF and OVA, and was abolished by Src inhibition. In addition, Erk1/2 was phosphorylated by EGF or by co-treatment with EGF and OVA; this was abolished by an EGF receptor inhibitor, but not by Src inhibition. These results suggested that OVA-induced EGF-related contraction was mediated by the Rho kinase-dependent inactivation of MLCP via two different signaling cascades: Src-dependent phosphorylation of the EGF receptor at Tyr-845 and EGF-dependent phosphorylation of Erk1/2.
Highlights
Smooth muscle contraction is regulated by Ca2+-dependent and Ca2+-independent pathways
We showed that epidermal growth factor (EGF) caused Ca2+ sensitization in the rat thoracic aorta by Rho kinase-dependent inactivation of myosin light chain (MLC) phosphatase (MLCP) through the extracellular signal-regulated kinase 1 and 2 (Erk1/2) kinase (MEK) pathway [31]
Since the aim of this study was to evaluate the roles of OVA and EGF in rat aortic smooth muscle contraction, we measured the contractile force in endothelium-denuded aortic rings in order to remove any nitric oxide (NO)-induced effects
Summary
Smooth muscle contraction is regulated by Ca2+-dependent and Ca2+-independent pathways. Vanadate-induced contraction of guinea pig ileal longitudinal smooth muscle was regulated by the activation of a Rho kinase-dependent pathway, resulting in an increase in MLC phosphorylation [29]. We reported that OVA caused Rho kinase-dependent contraction of the rat thoracic aorta and phosphorylation of MYPT1 in vascular smooth muscle cells [30]. These reports showed that inhibition of protein tyrosine phosphatases by vanadates induced smooth muscle contraction through Rho kinase-dependent inactivation of MLCP. The present study assessed whether activation of Src by OVA-mediated inhibition of tyrosine phosphatase was involved in EGF-related contraction of rat vascular smooth muscle
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