CaV3.1 Channels Facilitate Calcium Wave Generation and Myogenic Tone Development in Mouse Mesenteric Arteries
bioRxiv (Cold Spring Harbor Laboratory)(2023)
摘要
Abstract Background The myogenic response is the mechanism whereby intraluminal pressure elicits arterial constriction pursuant to the maintenance of tissue perfusion. Smooth muscle [Ca 2+ ] is a key determinant of constriction, a process intimately tied to L-type (Ca V 1.2) Ca 2+ channels. While important, other Ca 2+ channels, in particular T-type, are expressed and could contribute to pressure regulation within defined voltage ranges. This study examined the role of one T-type Ca 2+ channel using mesenteric arteries from C57BL/6 wild type and Ca V 3.1 -/- mice. Methods Patch-clamp electrophysiology, pressure myography, non-invasive blood pressure measurements and rapid Ca 2+ imaging were employed to define the Ca V 3.1 -/- phenotype relative to C57BL/6. Proximity ligation assay tested the closeness of Ca V 3.1 channels to inositol triphosphate receptors (IP 3 R). Nifedipine (0.3 μM) and 2-APB (50 μM) were used to block L-type Ca 2+ channels and IP 3 Rs, respectively. Results Initial experiments confirmed the absence of Ca V 3.1 expression and whole-cell current in global deletion mice, a change that coincided with a reduction in systemic blood pressure. Mesenteric arteries from Ca V 3.1 -/- mice produced less myogenic tone than C57BL/6, particularly at lower pressures (20-60 mmHg) where membrane potential is more hyperpolarized. This reduction in myogenic tone correlated with diminished Ca 2+ wave generation in the Ca V 3.1 -/- mice. These asynchronous events are dependent upon Ca 2+ release from the sarcoplasmic reticulum which is insensitive to L-type Ca 2+ channel blockade. A close physical association (<40 nm) between IP 3 R1 and Ca V 3.1 was confirmed by proximity ligation assay; blockade of IP 3 R in nifedipine-treated C57BL/6 arteries rendered a Ca V 3.1 -/- contractile phenotype. Conclusion Findings indicate that Ca 2+ influx through Ca V 3.1 channels contributes to myogenic tone development at hyperpolarized voltages by triggering a Ca 2+ -induced Ca 2+ release mechanism tied to the sarcoplasmic reticulum. This study helps establish Ca V 3.1 as a potential therapeutic target in the control of blood pressure.
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关键词
myogenic tone development,calcium,ca<sub>v</sub>31
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