Identification of Sodium/Myo-Inositol Transporter 1 as a Major Determinant of Arterial Contractility

As the sodium/myo-inositol transporter (SMIT1) is a positive regulator of Kv7.4/7.5 channels in arterial smooth muscle, we postulated that altering SMIT1 expression could have a major impact upon vascular reactivity. Consequently, this study aimed to characterize the effects of changes of SMIT1 membrane abundance on vascular tone in 2nd order mesenteric arteries and left anterior coronary arteries from WistarHan rats and identify the molecular mechanisms involved. Morpholino-mediated knockdown of SMIT1 enhanced U46619- and methoxamine-mediated contractions of mesenteric artery while impairing relaxations to the Kv7 activator ML213, isoprenaline and Calcitonin Gene Related Peptide (CGRP). Conversely, augmenting SMIT1 membrane abundance by raising external osmolarity with 150 mM raffinose impaired receptor-mediated contractions of mesenteric and coronary arteries, hyperpolarized the membrane potential and augmented relaxations to ML213 and adenosine. 1 h incubation in raffinose increased heterologously expressed Kv7.4-generated K+ currents in a SMIT1-dependent manner. Proximity ligation assays revealed that raffinose incubation increased the association of SMIT-Kv7.4/7.5 as well as Kv7.4 with Gβγ subunits. The SGK1 inhibitor EMD638683 prevented the raffinose-induced increase in SMIT1 and the anti-contractile effect. Toggling the membrane abundance of SMIT1 had a dramatic effect on the arterial response to vasoconstrictors and vasodilators mediated by greater coordination of Kv7 channels and Gβγ subunits. This work identified SMIT1-Kv7 channel complexes and SGK1 regulation as key modulators of arterial responsiveness.