Oxidative Regulation of Vascular Cav1.2 Channels Triggers Vascular Dysfunction in Hypertension-Related Disorders

Abstract

Blood pressure is determined by cardiac output and peripheral vascular resistance. The L-type voltage-gated Ca²⁺ (Ca_v1.2) channel in small arteries and arterioles plays an essential role in regulating Ca²⁺ influx, vascular resistance, and blood pressure. Hypertension and preeclampsia are characterized by high blood pressure. In addition, diabetes has a high prevalence of hypertension. The etiology of these disorders remains elusive, involving the complex interplay of environmental and genetic factors. Common to these disorders are oxidative stress and vascular dysfunction. Reactive oxygen species (ROS) derived from NADPH oxidases (NOXs) and mitochondria are primary sources of vascular oxidative stress, whereas dysfunction of the Ca_v1.2 channel confers increased vascular resistance in hypertension. This review will discuss the importance of ROS derived from NOXs and mitochondria in regulating vascular Ca_v1.2 and potential roles of ROS-mediated Ca_v1.2 dysfunction in aberrant vascular function in hypertension, diabetes, and preeclampsia.

Keywords: Cav1.2; gestational diabetes; hypertension; myogenic tone; preeclampsia; reactive oxygen species.

Figure 1

Topology of Ca_v1.2. Ca_v1.2 is formed by the pore-forming transmembrane α1c subunit, the intracellular β-subunit, the extracellular α2 subunit linked to the transmembrane δ1 subunit in smooth muscle cells.

Figure 2

Proposed mechanisms for regulating myogenic tone in small arteries and arterioles. Detailed information is discussed in the text. GPCR, G protein-coupled receptor, TRPV4, Transient receptor potential vanilloid-type 4; BK_Ca, large-conductance Ca²⁺-activated K⁺ channel; SR, sarcoplasmic reticulum; IP₃, inositol triphosphate; RyR, ryanodine receptor; CaM, calmodulin; MLCK, myosin light-chain kinase; MLC₂₀, 20 kD myosin light-chain.

Figure 3

ROS generation by NOXs and mitochondria and detoxification. In vascular smooth muscle cells, ROS is primarily produced by NOXs and mitochondria. NOXs catalyze the production of O₂^•− by transferring one electron to O₂ from NADPH. In mitochondria, O₂^•− is also produced from leaked electrons by Complexes I and III in the electronic transfer chain (ETC) during the electronic transfer. O₂^•− is dismutated to H₂O₂ by superoxide dismutase (SOD). H₂O₂ is subsequently decomposed to H₂O by catalase, glutathione peroxidase (GPX) and peroxiredoxin (PRX). O₂^•− can be released into the cytosol from mitochondria via the voltage-dependent anion channel (VADC) on the mitochondrial outer membrane, whereas H₂O₂ in mitochondria can be transported to the cytosol via diffusion or via aquaporins. O₂^•− reacts with nitro oxide (NO) to produce peroxynitrite (ONOO⁻), whereas H₂O₂ reacts with Fe²⁺ via the Fenton reaction to yield ^•OH.

Figure 4

Regulation of Ca_v1.2 by ROS microdomains. In vascular smooth muscle cells, ROS-derived from NOXs in plasma membrane and/or subcellular mitochondria in the immediate vicinity of Ca_v1.2 channels form ROS microdomains. Ca_v1.2 activity can be altered directly and indirectly by ROS. Within ROS microdomains, ROS can directly target cysteine residues in Ca_v1.2 to modify channel activity. In addition, ROS can also trigger ROS-dependent activation of PKC and/or c-Src. Activated PKC and c-Src in turn phosphorylate Ca_v1.2 and enhance channel activity.