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bioRxiv · 10.1101/2023.02.10.528095

CaV3.1 Channels Facilitate Calcium Wave Generation and Myogenic Tone Development in Mouse Mesenteric Arteries.

El-Lakany, M. A.·Haghbin, N.·Arora, N.·Hashad, A. M.·Mironova, G. Y.·Sancho, M.·Welsh, D. G.
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Abstract

BackgroundThe myogenic response is the mechanism whereby intraluminal pressure elicits arterial constriction pursuant to the maintenance of tissue perfusion. Smooth muscle [Ca2+] is a key determinant of constriction, a process intimately tied to L-type (CaV1.2) Ca2+ channels. While important, other Ca2+ 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 Ca2+ channel using mesenteric arteries from C57BL/6 wild type and CaV3.1-/- mice. MethodsPatch-clamp electrophysiology, pressure myography, non-invasive blood pressure measurements and rapid Ca2+ imaging were employed to define the CaV3.1-/- phenotype relative to C57BL/6. Proximity ligation assay tested the closeness of CaV3.1 channels to inositol triphosphate receptors (IP3R). Nifedipine (0.3 M) and 2-APB (50 M) were used to block L-type Ca2+ channels and IP3Rs, respectively. ResultsInitial experiments confirmed the absence of CaV3.1 expression and whole-cell current in global deletion mice, a change that coincided with a reduction in systemic blood pressure. Mesenteric arteries from CaV3.1-/- 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 Ca2+ wave generation in the CaV3.1-/- mice. These asynchronous events are dependent upon Ca2+ release from the sarcoplasmic reticulum which is insensitive to L-type Ca2+ channel blockade. A close physical association (<40 nm) between IP3R1 and CaV3.1 was confirmed by proximity ligation assay; blockade of IP3R in nifedipine-treated C57BL/6 arteries rendered a CaV3.1-/- contractile phenotype. ConclusionFindings indicate that Ca2+ influx through CaV3.1 channels contributes to myogenic tone development at hyperpolarized voltages by triggering a Ca2+-induced Ca2+ release mechanism tied to the sarcoplasmic reticulum. This study helps establish CaV3.1 as a potential therapeutic target in the control of blood pressure. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/528095v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1b3fe9forg.highwire.dtl.DTLVardef@11954borg.highwire.dtl.DTLVardef@607417org.highwire.dtl.DTLVardef@65964c_HPS_FORMAT_FIGEXP M_FIG C_FIG

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El-Lakany, M. A., Haghbin, N., Arora, N., Hashad, A. M., Mironova, G. Y., Sancho, M., Welsh, D. G.. 2023-02-13. CaV3.1 Channels Facilitate Calcium Wave Generation and Myogenic Tone Development in Mouse Mesenteric Arteries.. https://doi.org/10.1101/2023.02.10.528095

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