The Signaling Mechanisms Involved in Ca2+ Wave Generation and Myogenic Tone Regulation in Cerebral Arteries
Date
2013-07-15
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Abstract
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 signaling and the role of αvβ3-integrins in “sensing” intravascular pressure. More specifically, our work revealed that blocking this specific integrin receptor not only attenuated Ca2+ wave generation but also MLC20 phosphorylation and myogenic tone development. The final goal revealed that αvβ3-integrins facilitate pressure-induced Ca2+ waves and tone development by mobilizing downstream signaling proteins that included PLCγ1 and IP3R proteins. Overall, the findings arising from the three goals highlighted the mechanistic basis of pressure-inducing Ca2+ wave generation and myogenic tone development in resistance vasculature. This in turn will enlighten experimental approaches to control cerebral blood flow and will also provide crucial insight to treat cerebrovascular disease.
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Physiology
Citation
Mufti, R. E. (2013). The Signaling Mechanisms Involved in Ca2+ Wave Generation and Myogenic Tone Regulation in Cerebral Arteries (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/28378