Role for αvβ3 in the regulation of Ca2+ dynamics and myogenic tone development in rat cerebral arteries

Abstract

Intravascular pressure induces cerebral arterial tone by augmenting the activity of voltage‐gated Ca2+ channels (VGCC) and the generation of Ca2+ waves from the sarcoplasmic reticulum (SR). The signaling events that enable intravascular pressure to alter cytosolic Ca2+ dynamics and arterial tone remain uncertain. In this study we propose that the αvβ3‐integrin along with the downstream signaling proteins, focal adhesion kinase (FAK) and phospholipase C (PLCγ1), play a central role in the transduction of the myogenic response. In rat cerebral arteries denuded of endothelium, elevated intravascular pressure (20 to 80 mmHg) augmented FAK/PLCγ1 phosphorylation and the mobilization of Ca2+ from the extracellular space and the SR. These changes in cytosolic Ca2+ dynamics influenced the activity of myosin light chain kinase/phosphatase and consequently myogenic tone. Blocking αvβ3 with RGB peptides attenuated FAK/PLCγ1 phosphorylation, Ca2+ mobilization, the activation state of myosin light chain kinase/phosphatase and pressure‐induced tone. PLC inhibition with U73122 initiated a similar attenuating effect. In closing, this study highlights a key role for integrins, FAK and PLC in sensing changes in intravascular pressure, the mobilization of cytosolic Ca2+ and in the development of myogenic tone. Supported by the Natural Science and Engineering Research Council of Canada.