Epidermal growth factor induces Ca2+ sensitization through Rho-kinase-dependent phosphorylation of myosin phosphatase target subunit 1 in vascular smooth muscle

• Published in: European journal of pharmacology Vol. 762; pp. 89 - 95
• Main Authors: Sasahara, Tomoya, Okamoto, Hiroshi, Ohkura, Natsumi, Kobe, Asami, Yayama, Katsutoshi
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 05-09-2015
• Subjects: Epidermal growth factor; Myosin light chain phosphatase; Myosin phosphatase target subunit 1; Rho-kinase; Smooth muscle; Vasoconstriction; Rho-kinase; Smooth muscle; Myosin phosphatase target subunit 1; Epidermal growth factor; Myosin light chain phosphatase; Vasoconstriction
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2015.05.042

We previously found that the protein tyrosine phosphatase inhibitor orthovanadate evoked a vasoconstrictor effect in rat aortas via Rho-kinase-dependent inactivation of myosin light chain phosphatase (MLCP) downstream of epidermal growth factor (EGF) receptor signaling. To determine whether the direct activation of EGF receptor by EGF also induces Rho-kinase-dependent vasoconstriction, isometric tension changes were measured in rat aortic rings without endothelium. Although EGF did not produce a contractile effect, the Ca2+-induced force in Ca2+-depleted rings significantly increased after treatment with 100nM EGF, suggesting that EGF induces Ca2+ sensitization by MLCP inactivation. In addition, EGF induced the activation of Rho-kinase and phosphorylation of myosin phosphatase target subunit 1 (MYPT1) in rat aortic smooth muscle cells (VSMCs). The effects of EGF on Ca2+ sensitivity in aortas and MYPT1 phosphorylation in VSMCs were blocked by inhibitors of EGF receptor (AG1478), Rho-kinase (Y27632), extracellular signal-regulated kinase 1/2 (Erk1/2; FR180204), and mitogen/extracellular signal-regulated kinase (MEK; PD98059), but not by inhibitors of p38 kinase (SB203580) and c-Jun amino-terminal kinase (AS601245). EGF-induced Erk1/2 phosphorylation was not abrogated by the Rho-kinase inhibitor, suggesting that Rho-kinase-dependent phosphorylation of MYPT1 is downstream of EGF receptor/MEK/Erk1/2 signaling. These results suggest that EGF induces Ca2+ sensitization in vascular smooth muscle by Rho-kinase-dependent inactivation of MLCP mediated by the EGF receptor/MEK/Erk1/2 pathway.