The Signaling Mechanisms Involved in Ca2+ Wave Generation and Myogenic Tone Regulation in Cerebral Arteries

TL;DRAbstract

In the cerebral vasculature, the myogenic response plays an essential role in maintaining constant blood flow in an environment where intravascular pressure is constantly changing. This key biological response depends in part on a rise in cytosolic [Ca2+], an event often ascribed to arterial depolarization and the activation of voltage gated Ca2+ channels. While extracellular Ca2+ influx is important, a role for internal SR store release remains uncertain. The overall objective of this thesis was to clarify the mechanistic relationship between intravascular pressure, SR Ca2+ wave mobilization, cellular signaling and myogenic tone development. In the first of three defined goals, we showed for the first time that elevated intravascular pressure mobilizes SR Ca2+ waves in a voltage-insensitive manner. It was further noted that these SR-driven events contribute to MLC20 phosphorylation and tone development by modulating both MLCK and MLCP activity. The second goal focused on upstream sign

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