Role of Ca V 3.1 Channels in Myogenic Tone and Blood Pressure Regulation in Mouse Mesenteric Arteries

Abstract

The myogenic response is a fundamental mechanism whereby intraluminal pressure elicits arterial constriction pursuant to maintenance of tissue perfusion. Smooth muscle [Ca2+] is a key determinant of constriction, a process intimately tied to L-type (CaV1.2) Ca2+ channel activity. While important, other Ca2+ channels are expressed and could contribute to pressure regulation within defined voltage ranges. In this regard, this study examined the role of T-type Ca2+ channels, using mesenteric arterioles from wild type (WT) and CaV3.1-/- mice. Using pressure myography, experiments first revealed that CaV3.1-/- arterioles displayed decidedly less myogenic tone than WT, particular at lower pressures (20 – 60 mmHg) where membrane potential is hyperpolarized. We next showed with rapid Ca2+ imaging that reduced myogenic tone in CaV3.1-/- arteries resulted from diminished Ca2+ waves generation, asynchronous events dependent upon Ca2+ release from the sarcoplasmic reticulum. In contrast, blockade of L-type Ca2+ channels with nifedipine (200 nM) had no effect on Ca2+ waves, akin to previous findings. The proximity ligation assay confirmed a close association (<40 nm) between IP3R and CaV3.1, in WT and not knockout arterioles. In whole animals, this diminishment of myogenic tone coincided with a reduction in systemic blood pressure at rest. Intriguingly, this hypotension response did not impact blood pressure response to chronic AngII infusion. Taken together, this data suggests that CaV3.1 channels are contributors to tone development at low intraluminal pressures and that this effect is indirect through a Ca2+-induced Ca2+ release mechanism involving the sarcoplasmic reticulum. Further experiments are being extended to define the role of CaV3.1 in other pathophysiological models.