AbstractBackgroundThe 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 μM) and 2-APB (50 μM) 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.