Abstract
Angiotensin II (Ang II) induces vasoconstriction through myosin light chain (MLC) kinase activation and MLC phosphatase inactivation via phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) by Rho kinase. However, the detailed mechanism underlying Rho kinase activation by Ang II is still unknown. We investigated the mechanism of Ang II-induced vasoconstriction mediated by Rho kinase in pressure-overloaded rat thoracic aortas. Pressure-overloaded rats were produced by coarctation of the suprarenal abdominal aorta in four-week-old male Wistar rats. The contractile response to Ang II was significantly enhanced in the pressure-overloaded rats. Ang II-induced vasoconstriction was attenuated by inhibitors of Rho kinase, extracellular signal-regulated kinase 1 and 2 (Erk1/2), and epidermal growth factor receptor (EGFR) in both the sham-operated and pressure-overloaded rats. The Ang II-induced vasoconstriction was attenuated by a Janus kinase 2 (JAK2) inhibitor in only the pressure-overloaded rats. The protein levels of MYPT1 and JAK2 increased only in the pressure-overloaded rat thoracic aortas. These results suggested that Ang II-induced contraction is mediated by Rho kinase activation via EGFR, Erk1/2, and JAK2 in pressure-overloaded rat thoracic aortas. Moreover, Ang II-induced contraction was enhanced in pressure-overloaded rats probably because the protein levels of MYPT1 and JAK2 increased in the thoracic aortas.
Highlights
Hypertension is associated with endothelial dysfunction and enhanced vascular reactivity to vasoconstrictor stimuli
Angiotensin II (Ang II)-induced contraction was enhanced in pressure-overloaded rats probably because the protein levels of myosin phosphatase targeting subunit 1 (MYPT1) and Janus kinase 2 (JAK2) increased in the thoracic aortas
Rho kinase is activated by RhoA, a member of the Rho family of small GTPase-binding protein, that is activated by guanine nucleotide exchange factors (GEFs)
Summary
Hypertension is associated with endothelial dysfunction and enhanced vascular reactivity to vasoconstrictor stimuli. Pro-hypertensive stimuli, such as activation of the renin-angiotensin system, stimulate vascular smooth muscle cell (VSMC) signaling, which promotes vasoconstriction, vascular hypertrophy, fibrosis, inflammation, and calcification, processes that underlie vascular functional, structural, and mechanical changes in hypertension [1]. Angiotensin II (Ang II) is a key factor in the development of hypertension and induces vasoconstriction via type-1 (AT1 ) receptor which involves the increase in intracellular Ca2+. Increase in intracellular Ca2+ concentration forms a Ca2+/calmodulin complex, which activates myosin light chain (MLC) kinase (MLCK), causes MLC phosphorylation, and subsequent smooth muscle contraction. Ang II activates Rho kinase and causes MLC phosphatase (MLCP) inactivation through phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) and leading to the Ca2+ sensitization and vasoconstriction [2,3]. The detailed mechanism of Rho kinase activation by Ang II is still unknown
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
