Vascular Dysfunction in Diabetes Mellitus

Abstract

Vascular smooth muscle membrane potential is a key determinant of vessel tone primarily through regulation of voltage-dependent calcium channels (VDCCs). The opening probability of VDCCs is increased by membrane depolarization, facilitating influx of calcium and producing contraction of vascular smooth muscle cells (VSMCs). Control of membrane potential and VDCC activity is orchestrated by a complex series of signals that occur just below the sarcolemmal membrane. Article, see p 607 Large-conductance calcium-activated potassium channels (also known as maxi-K or BK channels) play a pivotal role in modulating vasomotor tone in both health and disease. BK channels, expressed on VSMCs, act as breaks for the increase in vascular tone that occurs after membrane depolarization and elevation of cytosolic calcium. An intracellular rise in cytosolic calcium through VDCC leads to activation of ryanodine receptors that release quanta of calcium from the sarcoplasmic reticulum (calcium sparks). It is these intracellularly generated sparks that elevate local submembrane concentrations of calcium and activate BK channels which increase potassium conductance and lower membrane potential.1 This reduces opening of VDCCs, thus modulating contraction (Figure2). Figure. Pathways for activation and modulation of vascular large-conductance calcium-activated potassium (BK) channels . Diabetes mellitus reduces BK channel activity by ≥3 mechanisms. First, as demonstrated by Nystoriak et al,2 through activation of calcineurin, dephosphorylated nuclear factor of activated T cells, c3 isoform (NFATc3) enters the nucleus where it inhibits transcription of the β1 subunit of BK, thereby reducing BK sensitivity to calcium. Second, diabetes mellitus–induced elevations in reactive oxygen species (ROS), particularly hydrogen peroxide, directly oxidize cysteine residues in the bowl region of the α subunit of BK to reduce opening. Finally, reduced insulin activation of phosphoinositol-3-kinase (PI3) kinase in diabetes mellitus reduces phosphorylation of forkhead box O family transcription factor (FOXO)-3a, allowing nuclear localization and transcription of f-box only protein …