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- W4225392874 abstract "Vascular smooth muscle cells (VSMCs) tune blood flow delivery through G protein-coupled receptor (GPCR) associated signaling pathways and two general contractile mechanisms. The first, electromechanical coupling ties membrane potential (VM ) to cytosolic [Ca2+ ] via voltage-sensitive L-type Ca2+ channels. The second-independent of voltage-centers on mechanisms of Ca2+ sensitization via Rho kinase and Protein Kinase C (PKC). While untested, agonists presumably activate both, with their relative contribution remaining static across concentration range. We hypothesize that voltage-dependent mechanisms proceed voltage-independent, and this order is contingent on the mode of agonist application. Mouse mesenteric/cerebral arteries mounted in a pressure myograph (60 mmHg) were globally or focally exposed to GPCR agonists (U46619 and Phenylephrine) and vasomotor responses, intercellular [Ca2+ ] levels, and VM monitored. Global application of either agonists increased arterial tone in a concentration dependent manner. Subsequent Nifedipine (L-type Ca2+ channel blocker) application attenuated constrictive responses, particularly at the lower agonist concentrations. The remaining voltage-independent constriction was blocked by Calphostin C (PKC inhibitor). While these findings highlight a hierarchical arrangement (voltage-dependent preceding voltage-independent), this order is not static. Stimulating a reduced number of VSMCs through focal agonist application, induces localized vasomotor responses that do not conduct across the arteriole or alter intercellular [Ca2+ ] or VM . Such focal responses could bypass electromechanical coupling owing to insufficient charge to change VM . Thus, this response is heavily dependent on Ca2+ sensitization mechanisms. Western blot analysis indicates that PKCα and PKCδ are likely the key regulatory isoforms in agonist-induced constriction. Ongoing work is focused on translocation of PKCα and PKCδ and phosphorylation state of their key downstream targets including MYPT1, CPI-17, Caldesmon, and HSP27. In summary, our findings reveal a hierarchical but malleable contractile arrangement in VSMCs whereby voltage-dependent signaling precedes voltage-independent, as long as sufficient smooth muscle cells are activated. These findings are of particular translational value to the pathobiology/management of cerebral vasospasm." @default.
- W4225392874 created "2022-05-05" @default.
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- W4225392874 date "2022-05-01" @default.
- W4225392874 modified "2023-10-16" @default.
- W4225392874 title "Investigating the Role of PKC‐delta in Voltage‐Independent Contractile Pathways in Mouse Resistance Arteries" @default.
- W4225392874 doi "https://doi.org/10.1096/fasebj.2022.36.s1.r3929" @default.
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