Activation of KV7 channels stimulates vasodilatation of human placental chorionic plate arteries.

INTRODUCTION Potassium (K(+)) channels are key regulators of vascular smooth muscle cell (VSMC) excitability. In systemic small arteries, Kv7 channel expression/activity has been noted and a role in vascular tone regulation demonstrated. We aimed to demonstrate functional Kv7 channels in human fetoplacental small arteries. METHODS Human placental chorionic plate arteries (CPAs) were obtained at term. CPA responses to Kv7 channel modulators was determined by wire myography. Presence of Kv7 channel mRNA (encoded by KCNQ1-5) and protein expression were assessed by RT-PCR and immunohistochemistry/immunofluorescence, respectively. RESULTS Kv7 channel blockade with linopirdine increased CPA basal tone and AVP-induced contraction. Pre-contracted CPAs (AVP; 80 mM K(+) depolarization solution) exhibited significant relaxation to flupirtine, retigabine, the acrylamide (S)-1, and (S) BMS-204352, differential activators of Kv7.1 - Kv7.5 channels. All CPAs assessed expressed KCNQ1 and KCNQ3-5 mRNA; KCNQ2 was expressed only in a subset of CPAs. Kv7 protein expression was confirmed in intact CPAs and isolated VSMCs. DISCUSSION Kv7 channels are present and active in fetoplacental vessels, contributing to vascular tone regulation in normal pregnancy. Targeting these channels may represent a therapeutic intervention in pregnancies complicated by increased vascular resistance.

[1]  M. Maclean,et al.  Treatment with the Kv7 potassium channel activator flupirtine is beneficial in two independent mouse models of pulmonary hypertension , 2009, British journal of pharmacology.

[2]  W. F. Jackson,et al.  Potassium Channels in the Peripheral Microcirculation , 2005, Microcirculation.

[3]  S. Burbidge,et al.  Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine. , 2000, Molecular pharmacology.

[4]  M. Schwake,et al.  Expression profile and characterisation of a truncated KCNQ5 splice variant. , 2008, Biochemical and biophysical research communications.

[5]  B. Horowitz,et al.  Molecular Variants of KCNQ Channels Expressed in Murine Portal Vein Myocytes: A Role in Delayed Rectifier Current , 2003, Circulation research.

[6]  J. Williams,et al.  K+ channel inhibition modulates the biochemical and morphological differentiation of human placental cytotrophoblast cells in vitro. , 2008, American journal of physiology. Regulatory, integrative and comparative physiology.

[7]  W. Giles,et al.  Uteroplacental blood flow velocity‐time waveforms in normal and complicated pregnancy , 1985, British journal of obstetrics and gynaecology.

[8]  J. Kingdom,et al.  Pathology and clinical implications of abnormal umbilical artery Doppler waveforms , 1997, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[9]  Jin Han,et al.  Physiological roles of K+ channels in vascular smooth muscle cells. , 2008, Journal of smooth muscle research = Nihon Heikatsukin Gakkai kikanshi.

[10]  M. Harhun,et al.  Expression and function of the K+ channel KCNQ genes in human arteries , 2011, British journal of pharmacology.

[11]  A. Mackie,et al.  Cardiovascular KCNQ (Kv7) Potassium Channels: Physiological Regulators and New Targets for Therapeutic Intervention , 2008, Molecular Pharmacology.

[12]  M. Wareing,et al.  Functional evidence for oxygen-sensitive voltage-gated potassium channels in human placental vasculature. , 2010, Placenta.

[13]  P. Baker,et al.  Altered Potassium Channel Expression in the Human Placental Vasculature of Pregnancies Complicated by Fetal Growth Restriction , 2008, Hypertension in pregnancy.

[14]  M. Schwake,et al.  Bimodal effects of the Kv7 channel activator retigabine on vascular K+ currents , 2008, British journal of pharmacology.

[15]  Characterisation of K+ Channels in Human Fetoplacental Vascular Smooth Muscle Cells , 2013, PloS one.

[16]  R. L. A. Ekskine,et al.  Umbilical artery blood flow characteristics in normal and growth‐retarded fetuses. , 1985 .

[17]  J. A. van der Laak,et al.  Impaired KATP channel function in the fetoplacental circulation of patients with type 1 diabetes mellitus. , 2005, American journal of obstetrics and gynecology.

[18]  M. Wareing,et al.  Expression of an electrically silent voltage-gated potassium channel in the human placenta , 2012, Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology.

[19]  M. Wareing.  Effects of oxygenation and luminal flow on human placenta chorionic plate blood vessel function , 2012, The journal of obstetrics and gynaecology research.

[20]  H. Schulman,et al.  Umbilical artery velocity waveforms and intrauterine growth retardation. , 1985, American journal of obstetrics and gynecology.

[21]  M. Taggart,et al.  Glibenclamide inhibits agonist-induced vasoconstriction of placental chorionic plate arteries. , 2006, Placenta.

[22]  M. Schwake,et al.  Molecular expression and pharmacological identification of a role for Kv7 channels in murine vascular reactivity , 2007, British journal of pharmacology.

[23]  M. Taggart,et al.  Expression and function of potassium channels in the human placental vasculature. , 2006, American journal of physiology. Regulatory, integrative and comparative physiology.

[24]  J. Glazier,et al.  SNAT4 isoform of system A amino acid transporter is expressed in human placenta. , 2006, American journal of physiology. Cell physiology.

[25]  L. Cribbs,et al.  Vasopressin stimulates action potential firing by protein kinase C-dependent inhibition of KCNQ5 in A7r5 rat aortic smooth muscle cells. , 2007, American journal of physiology. Heart and circulatory physiology.

[26]  G. Fried,et al.  Nitric oxide donors mediate vasodilation in human placental arteries partly through a direct effect on potassium channels. , 2006, Placenta.

[27]  S. Segal,et al.  Spreading the signal for vasodilatation: implications for skeletal muscle blood flow control and the effects of ageing , 2012, The Journal of physiology.

[28]  M. Wareing,et al.  Relaxation of human placental arteries and veins by ATP‐sensitive potassium channel openers , 2007, European journal of clinical investigation.

[29]  L. Cribbs,et al.  Vascular KCNQ Potassium Channels as Novel Targets for the Control of Mesenteric Artery Constriction by Vasopressin, Based on Studies in Single Cells, Pressurized Arteries, and in Vivo Measurements of Mesenteric Vascular Resistance , 2008, Journal of Pharmacology and Experimental Therapeutics.

[30]  R. L. Erskine,et al.  Umbilical artery blood flow characteristics in normal and growth-retarded fetuses. , 1986, British journal of obstetrics and gynaecology.

[31]  A. Gurney,et al.  KCNQ Modulators Reveal a Key Role for KCNQ Potassium Channels in Regulating the Tone of Rat Pulmonary Artery Smooth Muscle , 2009, Journal of Pharmacology and Experimental Therapeutics.

[32]  M. Nelson,et al.  Physiological roles and properties of potassium channels in arterial smooth muscle. , 1995, The American journal of physiology.

[33]  S. Ohya,et al.  New tricks for old dogs: KCNQ expression and role in smooth muscle , 2009, British journal of pharmacology.

[34]  Nicole Schmitt,et al.  The acrylamide (S)-1 differentially affects Kv7 (KCNQ) potassium channels , 2006, Neuropharmacology.

[35]  Lubo Zhang,et al.  Function and regulation of large conductance Ca(2+)-activated K+ channel in vascular smooth muscle cells. , 2012, Drug discovery today.

[36]  M. Bara,et al.  Calcium channels, potassium channels and membrane potential of smooth muscle cells of human allantochorial placental vessels. , 1999, Bioelectrochemistry and bioenergetics.

[37]  B. Trudinger,et al.  Umbilical and uterine artery flow velocity waveforms in pregnancy associated with major fetal abnormality , 1985, British journal of obstetrics and gynaecology.

[38]  A. Olschewski.  Targeting TASK-1 channels as a therapeutic approach. , 2010, Advances in experimental medicine and biology.

[39]  I. Crocker,et al.  Characterization of small arteries isolated from the human placental chorionic plate. , 2002, Placenta.

[40]  M. Graham,et al.  Isolation and Culture of Arterial Smooth Muscle Cells From Human Placenta , 2004, Hypertension.

[41]  S. Archer,et al.  Potassium channel diversity in vascular smooth muscle cells. , 1997, Canadian journal of physiology and pharmacology.

[42]  S. Archer,et al.  Hypoxic fetoplacental vasoconstriction in humans is mediated by potassium channel inhibition. , 2002, American journal of physiology. Heart and circulatory physiology.

[43]  D. A. Brown,et al.  Activation of Expressed KCNQ Potassium Currents and Native Neuronal M-Type Potassium Currents by the Anti-Convulsant Drug Retigabine , 2001, The Journal of Neuroscience.

[44]  S. Olesen,et al.  K(v)7 channels: function, pharmacology and channel modulators. , 2006, Current topics in medicinal chemistry.

[45]  P. Baker,et al.  Reactivity of Human Placental Chorionic Plate Vessels from Pregnancies Complicated by Intrauterine Growth Restriction (IUGR)1 , 2006, Biology of reproduction.