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Reduced Mechanical Stretch Induces Enhanced Endothelin B Receptor‐Mediated Contractility via Activation of Focal Adhesion Kinase and Extracellular Regulated Kinase 1/2 in Cerebral Arteries from Rat
Author(s) -
Spray Stine,
Rasmussen Marianne N. P.,
Skovsted Gry F.,
Warfvinge Karin,
Sheykhzade Majid,
Edvinsson Lars
Publication year - 2016
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12553
Subject(s) - myograph , contractility , focal adhesion , receptor , mapk/erk pathway , extracellular , endothelin 1 , microbiology and biotechnology , endocrinology , biology , medicine , agonist , kinase , chemistry , signal transduction , contraction (grammar)
Cerebral ischaemia results in enhanced endothelin B ( ET B ) receptor‐mediated contraction and receptor protein expression in the affected cerebrovascular smooth muscle cells ( SMC ). Organ culture of cerebral arteries is a method to induce similar alterations in ET B receptor expression. We suggest that rapid and sustained reduction in wall tension/stretch is a possible trigger mechanism for this vascular remodelling. Isolated rat middle cerebral artery ( MCA ) segments were incubated in a wire myograph with or without mechanical stretch, prior to assessment of their contractile response to the selective ET B receptor agonist sarafotoxin 6c. The involvement of extracellular regulated kinase ( ERK ) 1/2 and focal adhesion kinase ( FAK ) was studied by their specific inhibitors U0126 and PF ‐228, respectively. Compared with their stretched counterparts, unstretched MCA segments showed a significantly increased ET B receptor‐mediated contractile response after 12 hr of incubation, which was attenuated by either U0126 or PF ‐228. The functionally increased ET B ‐mediated contractility could be attributed to two different mechanisms: (i) a difference in ET B receptor localization from primarily endothelial expression to SMC expression and (ii) an increased calcium sensitivity of the SMC s due to an increased expression of the calcium channel transient receptor potential canonical 1. Collectively, our results present a possible mechanism linking lack of vessel wall stretch/tension to changes in ET B receptor‐mediated contractility via triggering of an early mechanosensitive signalling pathway involving ERK 1/2 and FAK signalling. A mechanism likely to be an initiating factor for the increased ET B receptor‐mediated contractility found after cerebral ischaemia.