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

Autor: Lars Edvinsson, Gry Freja Skovsted, Majid Sheykhzade, Stine Spray, Marianne N. P. Rasmussen, Karin Warfvinge
Rok vydání: 2015
Předmět:
MAPK/ERK pathway
Male
medicine.medical_specialty
Middle Cerebral Artery
Cerebral arteries
Myocytes
Smooth Muscle
Viper Venoms
030204 cardiovascular system & hematology
Biology
Quinolones
Toxicology
Contractility
Focal adhesion
03 medical and health sciences
0302 clinical medicine
Internal medicine
Nitriles
medicine
Butadienes
Animals
Vasoconstrictor Agents
Sulfones
Enzyme Inhibitors
Rats
Wistar
Receptor
TRPC Cation Channels
Pharmacology
Mitogen-Activated Protein Kinase 3
Dose-Response Relationship
Drug
General Medicine
musculoskeletal system
Receptor
Endothelin B
Rats
Endocrinology
Focal Adhesion Protein-Tyrosine Kinases
cardiovascular system
Signal transduction
Endothelin receptor
030217 neurology & neurosurgery
circulatory and respiratory physiology
Myograph
Muscle Contraction
Signal Transduction
Zdroj: Basicclinical pharmacologytoxicology. 119(1)
ISSN: 1742-7843
Popis: Cerebral ischaemia results in enhanced endothelin B (ETB ) 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 ETB 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 ETB 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 ETB receptor-mediated contractile response after 12 hr of incubation, which was attenuated by either U0126 or PF-228. The functionally increased ETB -mediated contractility could be attributed to two different mechanisms: (i) a difference in ETB receptor localization from primarily endothelial expression to SMC expression and (ii) an increased calcium sensitivity of the SMCs 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 ETB receptor-mediated contractility via triggering of an early mechanosensitive signalling pathway involving ERK1/2 and FAK signalling. A mechanism likely to be an initiating factor for the increased ETB receptor-mediated contractility found after cerebral ischaemia.
Databáze: OpenAIRE
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