Contribution of Kv Channels to Phenotypic Remodeling of Human Uterine Artery Smooth Muscle Cells

Abstract

Abstract-Vascular smooth muscle cells (VSMCs) perform diverse functions that can be classified into contractile and synthetic (or proliferating). All of these functions can be fulfilled by the same cell because of its capacity of phenotypic modulation in response to environmental changes. The resting membrane potential is a key determinant for both contractile and proliferating functions. Here, we have explored the expression of voltage-dependent K ϩ (Kv) channels in contractile (freshly dissociated) and proliferating (cultured) VSMCs obtained from human uterine arteries to establish their contribution to the functional properties of the cells and their possible participation in the phenotypic switch. We have studied the expression pattern (both at the mRNA and at the protein level) of Kv␣ subunits in both preparations as well as their functional contribution to the K ϩ currents of VSMCs. Our results indicate that phenotypic remodeling associates with a change in the expression and distribution of Kv channels. Whereas Kv currents in contractile VSMCs are mainly performed by Kv1 channels, Kv3.4 is the principal contributor to K ϩ currents in cultured VSMCs. Furthermore, selective blockade of Kv3.4 channels resulted in a reduced proliferation rate, suggesting a link between Kv channels expression and phenotypic remodeling. T he vascular smooth muscle cells (VSMCs) of mature animals are highly specialized cells whose main function is contraction. Although during vasculogenesis, the principal role of VSMCs is proliferation and synthesis of the matrix components of the vessel wall, differentiated VSMCs proliferate at an extremely low rate and express a unique repertoire of contractile proteins, ion channels, and signaling molecules required for contraction. However, VSMCs can undergo relatively rapid and reversible phenotypic changes in response to local environmental conditions. Accelerated proliferation of VSMCs is known to play a key role in atherosclerotic plaque formation and postangioplasty restenosis and is a common feature in hypertensive arteries. 1 VSMCs express a large repertoire of ion channels and membrane receptors that vary widely among different vascular beds and are key determinants of the electrical and contractile responses of the cells. [2][3][4][5] Although release of intracellular Ca 2ϩ is necessary for effective contraction, Ca 2ϩ influx through voltage-activated Ca 2ϩ (Cav) channels is responsible for initiating contraction, making resting membrane potential (E m ) a primary determinant of vascular smooth muscle tone. 4 Membrane depolarization opens Cav and raises [Ca 2ϩ ] i , and cytosolic-free Ca 2ϩ serves, in turn, as a critical signal transduction element in a variety of cell functions, such as contraction, migration, proliferation, and gene expression. 6 -8 There is increasing evidence showing that K ϩ channels may have an important role in dedifferentiation and proliferation of VSMCs. Modulating E m , K ϩ channels can affect not only Ca 2ϩ influx, a well-established factor influen...

Potassium Channels and Proliferation of Vascular Smooth Muscle Cells

“…By having a new target K ϩ channel in smooth muscle, it may be possible, through comparative studies using genomic and proteomic approaches, to define commonalities among different K ϩ channels and proliferation in one cell type. Finally, the study by Miguel-Velado and colleagues 10 reinforces the notion that proliferating smooth muscle cells in culture are a poor model system in which to study normal ion channel expression and physiological function.…”

“…4 -6 Studies from lymphocytes and tumor cells suggest that progress into G1 of the cell cycle requires K ϩ channelinduced membrane hyperpolarization. 8 Hyperpolarization does not appear to account for the impact of Kv3.4 channel expression in the study by Miguel-Velado et al, 10 because proliferating smooth muscle cells were found to be depolarized compared with freshly isolated cells. However, transient hyperpolarization associated with entrance into G1 was not excluded by Miguel-Velado et al, 10 as the cells studied were not synchronized and the cell cycle state in which membrane potential was measured was not assessed.…”

“…These K V channels also have been implicated in proliferation of an oral squamous cell carcinoma, 11,12 and their expression is increased in growth cones of retinal ganglion cells. 13 Although Kv3.4 channels, and other members of the voltage-gated K ϩ channel superfamily of K ϩ channels such as Kv1.3, 5,8 Kv10.1, and Kv11.1, 5 have been implicated in proliferation of other cell types, the study by Miguel-Velado and associates 10 is the first to suggest that the Kv3 family participates in proliferation of smooth muscle cells. This finding is significant for several reasons.…”

The non-excitable smooth muscle: Calcium signaling and phenotypic switching during vascular disease

“…While Kv1 channel members were the main contributors to the Kv currents in the human uterine contractile phenotype, proliferating VSMC upregulated Kv3.4 expression [92]; Kv3.4 is characterized by a rapid inactivation. Interestingly, selective blockade of Kv3.4 channels decreased VSMC proliferation [92]. Another study showed that pulmonary artery SMC proliferation is associated with a decrease in Kv1.5 currents [159].…”

Dichloroacetate Inhibits Vascular Remodeling and Increases Voltage-gate K+ Expression in a High-altitude-induced Pulmonary Artery Hypertension Rat Model

“…12,18,21,22) Previous studies have shown that chronic hypoxia decreases Kv gene expression. 1,2,10) Here, we showed that Kv1.5 and Kv2.1, the channels that participate in determining membrane potential in rat PASMCs, were downregulated in PASMCs during simulated HA.…”