Abstract
BKCa channels (large-conductance Ca2+-activated K+ channels) play a critical role in regulating vascular tone and blood pressure. These channels are present in the smooth muscle cells of blood vessels and are activated by voltage and increased intracellular Ca2+ concentration. More recently, the expression and activity of BKCa have been proposed to be relevant in endothelial cells, too, specifically in human umbilical vein endothelial cells (HUVECs), the more studied cell type in the fetoplacental circulation. The role of BKCa in endothelial cells is not well understood, but in HUVECs or placental endothelium, these channels could be crucial for vascular tone regulation during pregnancy as part of endothelium-derived hyperpolarization (EDH), a key mechanism for an organ that lacks nervous system innervation like the placenta.
In this review, we will discuss the evidence about the role of BKCa (and other Ca2+-activated K+ channels) in HUVECs and the placenta to propose a physiological mechanism for fetoplacental vascular regulation and a pathophysiological role of BKCa, mainly associated with pregnancy pathologies that present maternal hypertension and/or placental hypoxia, like preeclampsia.
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References
Aouache R, Biquard L, Vaiman D, Miralles F (2018) Oxidative stress in preeclampsia and placental diseases. Int J Mol Sci 19:E1496. https://doi.org/10.3390/ijms19051496
Apaza Valencia J (2014) Desarrollo placentario temprano: aspectos fisiopatológicos. Rev Peru Ginecol Obstet 60:131–140
Bae H, Kim T, Lim I (2021) Carbon monoxide activates large-conductance calcium-activated potassium channels of human cardiac fibroblasts through various mechanisms. Korean J Physiol Pharmacol Off J Korean Physiol Soc Korean Soc Pharmacol 25:227–237. https://doi.org/10.4196/kjpp.2021.25.3.227
Benham CD, Bolton TB (1986) Spontaneous transient outward currents in single visceral and vascular smooth muscle cells of the rabbit. J Physiol 381:385–406. https://doi.org/10.1113/jphysiol.1986.sp016333
Betts LC, Kozlowski RZ (2000) Electrophysiological effects of endothelin-1 and their relationship to contraction in rat renal arterial smooth muscle. Br J Pharmacol 130:787–796. https://doi.org/10.1038/sj.bjp.0703377
Boeldt DS, Bird IM (2017) Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia. J Endocrinol 232:R27–R44. https://doi.org/10.1530/JOE-16-0340
Brereton MF, Wareing M, Jones RL, Greenwood SL (2013) Characterisation of K+ channels in human fetoplacental vascular smooth muscle cells. PLoS One 8:e57451. https://doi.org/10.1371/journal.pone.0057451
Burgazli KM, Venker CJ, Mericliler M, Atmaca N, Parahuleva M, Erdogan A (2014) Importance of large conductance calcium-activated potassium channels (BKCa) in interleukin-1b-induced adhesion of monocytes to endothelial cells. Eur Rev Med Pharmacol Sci 18:646–656
Bychkov R, Pieper K, Ried C, Milosheva M, Bychkov E, Luft FC, Haller H (1999) Hydrogen peroxide, potassium currents, and membrane potential in human endothelial cells. Circulation 99:1719–1725. https://doi.org/10.1161/01.cir.99.13.1719
Cabrera L, Saavedra A, Rojas S, Cid M, Valenzuela C, Gallegos D, Careaga P, Basualto E, Haensgen A, Peña E, Rivas C, Vera JC, Gallardo V, Zúñiga L, Escudero C, Sobrevia L, Wareing M, González M (2016) Insulin induces relaxation and decreases hydrogen peroxide-induced vasoconstriction in human placental vascular bed in a mechanism mediated by calcium-activated potassium channels and L-arginine/nitric oxide pathways. Front Physiol 7:529. https://doi.org/10.3389/fphys.2016.00529
Castellucci M, Kaufmann P (2000) Basic structure of the villous trees. In: Benirschke K, Kaufmann P (eds) Pathology of the human placenta. Springer, New York, NY, pp 50–115. https://doi.org/10.1007/978-1-4757-4199-5_6
Chen D, Zheng J (2014) Regulation of placental angiogenesis. Microcirc N Y N 1994(21):15–25. https://doi.org/10.1111/micc.12093
Chen J, Gao Q, Jiang L, Feng X, Zhu X, Fan X, Mao C, Xu Z (2017) The NOX2-derived reactive oxygen species damaged endothelial nitric oxide system via suppressed BKCa/SKCa in preeclampsia. Hypertens. Res. Off. J. Jpn. Soc. Hypertens. 40:457–464. https://doi.org/10.1038/hr.2016.180
Chen G, Li Q, Yan J (2022) The leucine-rich repeat domains of BK channel auxiliary γ subunits regulate their expression, trafficking, and channel-modulation functions. J Biol Chem 298:101664. https://doi.org/10.1016/j.jbc.2022.101664
Dong D-L, Zhang Y, Lin D-H, Chen J, Patschan S, Goligorsky MS, Nasjletti A, Yang B-F, Wang W-H (2007) Carbon monoxide stimulates the Ca2(+)-activated big conductance k channels in cultured human endothelial cells. Hypertens Dallas Tex 1979(50):643–651. https://doi.org/10.1161/HYPERTENSIONAHA.107.096057
Faehling M, Koch ED, Raithel J, Trischler G, Waltenberger J (2001) Vascular endothelial growth factor-A activates Ca2+ −activated K+ channels in human endothelial cells in culture. Int J Biochem Cell Biol 33:337–346. https://doi.org/10.1016/s1357-2725(01)00021-8
Fallahi S, Houck JA, Euser AG, Julian CG, Moore LG, Lorca RA (2022) High altitude differentially modulates potassium channel-evoked vasodilatation in pregnant human myometrial arteries. J Physiol 600:5353–5364. https://doi.org/10.1113/JP283741
Félétou M (2009) Calcium-activated potassium channels and endothelial dysfunction: therapeutic options? Br J Pharmacol 156:545–562. https://doi.org/10.1111/j.1476-5381.2009.00052.x
Francis SH, Busch JL, Corbin JD (2010) cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol Rev 62:525–563. https://doi.org/10.1124/pr.110.002907
Gamper N, Ooi L (2015) Redox and nitric oxide-mediated regulation of sensory neuron Ion channel function. Antioxid Redox Signal 22:486–504. https://doi.org/10.1089/ars.2014.5884
Garland CJ, Dora KA (2021) Endothelium-dependent hyperpolarization: the evolution of myoendothelial microdomains. J Cardiovasc Pharmacol 78:S3–S12. https://doi.org/10.1097/FJC.0000000000001087
González M, Rivas JC (2020) L-arginine/nitric oxide pathway and KCa channels in endothelial cells: a mini-review. Vasc Biol. https://doi.org/10.5772/intechopen.93400
González M, Flores C, Pearson JD, Casanello P, Sobrevia L (2004) Cell signalling-mediating insulin increase of mRNA expression for cationic amino acid transporters-1 and -2 and membrane hyperpolarization in human umbilical vein endothelial cells. Pflugers Arch 448:383–394. https://doi.org/10.1007/s00424-004-1261-x
González M, Gallardo V, Rodríguez N, Salomón C, Westermeier F, Guzmán-Gutiérrez E, Abarzúa F, Leiva A, Casanello P, Sobrevia L (2011) Insulin-stimulated L-arginine transport requires SLC7A1 gene expression and is associated with human umbilical vein relaxation. J Cell Physiol 226:2916–2924. https://doi.org/10.1002/jcp.22635
He M, Li F, Yang M, Fan Y, Beejadhursing R, Xie Y, Zhou Y, Deng D (2018) Impairment of BKca channels in human placental chorionic plate arteries is potentially relevant to the development of preeclampsia. Hypertens Res Off J Jpn Soc Hypertens 41:126–134. https://doi.org/10.1038/hr.2017.99
Hu X-Q, Zhang L (2012) Function and regulation of large conductance Ca(2+)-activated K+ channel in vascular smooth muscle cells. Drug Discov Today 17:974–987. https://doi.org/10.1016/j.drudis.2012.04.002
Hu X-Q, Zhang L (2023) Ca2+-activated K+ channels and the regulation of the uteroplacental circulation. Int J Mol Sci 24:1349. https://doi.org/10.3390/ijms24021349
Hu X-Q, Dasgupta C, Chen M, Xiao D, Huang X, Han L, Yang S, Xu Z, Zhang L (2017) Pregnancy reprograms large-conductance Ca2+-activated K+ channel in uterine arteries. Hypertension 69:1181–1191. https://doi.org/10.1161/HYPERTENSIONAHA.117.09059
Hu X-Q, Dasgupta C, Xiao J, Yang S, Zhang L (2018) Long-term high altitude hypoxia during gestation suppresses large conductance Ca2+−activated K+ channel function in uterine arteries: a causal role for microRNA-210. J Physiol 596:5891–5906. https://doi.org/10.1113/JP276058
Imig JD (2016) Epoxyeicosatrienoic acids and 20-hydroxyeicosatetraenoic acid on endothelial and vascular function. Adv Pharmacol San Diego Calif 77:105–141. https://doi.org/10.1016/bs.apha.2016.04.003
Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333:1300–1303. https://doi.org/10.1126/science.1210597
Jaggar JH, Li A, Parfenova H, Liu J, Umstot ES, Dopico AM, Leffler CW (2005) Heme is a carbon monoxide receptor for large-conductance Ca2+−activated K+ channels. Circ Res 97:805–812. https://doi.org/10.1161/01.RES.0000186180.47148.7b
Kaczmarek LK, Aldrich RW, Chandy KG, Grissmer S, Wei AD, Wulff H (2017) International Union of Basic and Clinical Pharmacology. C. Nomenclature and properties of calcium-activated and sodium-activated potassium channels. Pharmacol Rev 69:1–11. https://doi.org/10.1124/pr.116.012864
Karadas B, Acar-Sahan S, Kantarci S, Uysal N, Horoz E, Kaya-Temiz T (2023) Comparison of relaxant effects of nifedipine and NS11021 on isolated umbilical arteries of healthy and preeclamptic pregnant women. Eur J Obstet Gynecol Reprod Biol 280:168–173. https://doi.org/10.1016/j.ejogrb.2022.12.009
Karumanchi SA, Maynard SE, Stillman IE, Epstein FH, Sukhatme VP (2005) Preeclampsia: a renal perspective. Kidney Int 67:2101–2113. https://doi.org/10.1111/j.1523-1755.2005.00316.x
Kestler HA, Janko S, Häußler U, Muche R, Hombach V, Höher M, Wiecha J (1998) A remark on the high-conductance calcium-activated potassium channel in human endothelial cells. Res Exp Med (Berl) 198:133–143. https://doi.org/10.1007/s004330050097
Kuhlmann CRW, Schäfer M, Li F, Sawamura T, Tillmanns H, Waldecker B, Wiecha J (2003) Modulation of endothelial Ca(2+)-activated K(+) channels by oxidized LDL and its contribution to endothelial proliferation. Cardiovasc Res 60:626–634. https://doi.org/10.1016/j.cardiores.2003.08.010
Kuhlmann CRW, Most AK, Li F, Münz BM, Schaefer CA, Walther S, Raedle-Hurst T, Waldecker B, Piper HM, Tillmanns H, Wiecha J (2005a) Endothelin-1-induced proliferation of human endothelial cells depends on activation of K+ channels and Ca+ influx. Acta Physiol Scand 183:161–169. https://doi.org/10.1111/j.1365-201X.2004.01378.x
Kuhlmann CR, Schaefer CA, Kosok C, Abdallah Y, Walther S, Lüdders DW, Neumann T, Tillmanns H, Schäfer C, Piper HM, Erdogan A (2005b) Quercetin-induced induction of the NO/cGMP pathway depends on Ca2+−activated K+ channel-induced hyperpolarization-mediated Ca2+−entry into cultured human endothelial cells. Planta Med 71:520–524. https://doi.org/10.1055/s-2005-864152
Lecarpentier E, Fournier T, Guibourdenche J, Gil S, Tsatsaris V (2015) La placenta humana. EMC - Ginecol-Obstet 51:1–19. https://doi.org/10.1016/S1283-081X(15)72835-3
Li J, He J, Yu C (2012) Chitosan oligosaccharide inhibits LPS-induced apoptosis of vascular endothelial cells through the BKCa channel and the p38 signaling pathway. Int J Mol Med 30:157–164. https://doi.org/10.3892/ijmm.2012.954
Li F-F, He M-Z, Xie Y, Wu Y-Y, Yang M-T, Fan Y, Qiao F-Y, Deng D-R (2017) Involvement of dysregulated IKCa and SKCa channels in preeclampsia. Placenta 58:9–16. https://doi.org/10.1016/j.placenta.2017.07.361
Luedders DW, Muenz BM, Li F, Rueckleben S, Tillmanns H, Waldecker B, Wiecha J, Erdogan A, Schaefer CA, Kuhlmann CRW (2006) Role of cGMP in sildenafil-induced activation of endothelial Ca2+−activated K+ channels. J Cardiovasc Pharmacol 47:365–370. https://doi.org/10.1097/01.fjc.0000206438.35477.f2
Martín P, Rebolledo A, Palomo ARR, Moncada M, Piccinini L, Milesi V (2014) Diversity of potassium channels in human umbilical artery smooth muscle cells. Reprod Sci 21:432–441. https://doi.org/10.1177/1933719113504468
Marzioni D, Tamagnone L, Capparuccia L, Marchini C, Amici A, Todros T, Bischof P, Neidhart S, Grenningloh G, Castellucci M (2004) Restricted innervation of uterus and placenta during pregnancy: evidence for a role of the repelling signal Semaphorin 3A. Dev Dyn Off Publ Am Assoc Anat 231:839–848. https://doi.org/10.1002/dvdy.20178
Mills TA, Wareing M, Shennan AH, Poston L, Baker PN, Greenwood SL (2009) Acute and chronic modulation of placental chorionic plate artery reactivity by reactive oxygen species. Free Radic Biol Med 47:159–166. https://doi.org/10.1016/j.freeradbiomed.2009.04.019
Nilius B, Riemann D (1990) Ion channels in human endothelial cells. Gen Physiol Biophys 9:89–111
Ogoyama M, Takahashi H, Suzuki H, Ohkuchi A, Fujiwara H, Takizawa T (2022) Non-coding RNAs and prediction of preeclampsia in the first trimester of pregnancy. Cell 11:2428. https://doi.org/10.3390/cells11152428
Park WS, Ko EA, Jung ID, Son YK, Kim HK, Kim N, Park SY, Hong KW, Park Y-M, Choi T-H, Han J (2008) APE1/Ref-1 promotes the effect of angiotensin II on Ca2+ −activated K+ channel in human endothelial cells via suppression of NADPH oxidase. Arch Pharm Res 31:1291–1301. https://doi.org/10.1007/s12272-001-2109-y
Prieto-Gómez R, Ottone NE, Bianchi H (2018) Morphological features of the human placenta and its free chorionic villi in normal pregnancies and those with diabetes and high blood pressure. Literature Review Int J Morphol 36:1183–1192. https://doi.org/10.4067/S0717-95022018000401183
Rada CC, Murray G, England SK (2014) The SK3 channel promotes placental vascularization by enhancing secretion of angiogenic factors. Am J Physiol Endocrinol Metab 307:E935–E943. https://doi.org/10.1152/ajpendo.00319.2014
Rodríguez I, González M (2014) Physiological mechanisms of vascular response induced by shear stress and effect of exercise in systemic and placental circulation. Front Pharmacol 5:209. https://doi.org/10.3389/fphar.2014.00209
Rojas S, Basualto E, Valdivia L, Vallejos N, Ceballos K, Peña E, Rivas C, Nualart F, Guzmán-Gutiérrez E, Escudero C, Toledo F, Sobrevia L, Cid M, González M (2020) The activity of IKCa and BKCa channels contributes to insulin-mediated NO synthesis and vascular tone regulation in human umbilical vein. Nitric Oxide Biol Chem 99:7–16. https://doi.org/10.1016/j.niox.2020.03.004
Sobrevia L, Nadal A, Yudilevich DL, Mann GE (1996) Activation of L-arginine transport (system y+) and nitric oxide synthase by elevated glucose and insulin in human endothelial cells. J Physiol 490(Pt 3):775–781. https://doi.org/10.1113/jphysiol.1996.sp021185
Turco MY, Moffett A (2019) Development of the human placenta. Dev Camb Engl 146:dev163428. https://doi.org/10.1242/dev.163428
Wang Y, Zhao S (2010) Structure of the placenta. Morgan & Claypool Life Sciences, Vascular Biology of the Placenta
Wareing M (2014) Oxygen sensitivity, potassium channels, and regulation of placental vascular tone. Microcirc. N. Y. N 1994(21):58–66. https://doi.org/10.1111/micc.12069
Wareing M, Greenwood SL (2011) Review: potassium channels in the human fetoplacental vasculature. Placenta 32(Suppl 2):S203–S206. https://doi.org/10.1016/j.placenta.2010.12.022
Watanapa WB, Theerathananon W, Akarasereenont P, Techatraisak K (2012) Effects of preeclamptic plasma on potassium currents of human umbilical vein endothelial cells. Reprod Sci 19:391–399. https://doi.org/10.1177/1933719111424434
Wiecha J, Reineker K, Reitmayer M, Voisard R, Hannekum A, Mattfeldt T, Waltenberger J, Hombach V (1998) Modulation of Ca2+−activated K+ channels in human vascular cells by insulin and basic fibroblast growth factor. Growth Horm. IGF res. Off. J. Growth Horm. Res Soc Int IGF Res Soc 8:175–181. https://doi.org/10.1016/s1096-6374(98)80108-1
Xu YC, Leung GPH, Wong PYD, Vanhoutte PM, Man RYK (2008) Kaempferol stimulates large conductance Ca2+ −activated K+ (BKCa) channels in human umbilical vein endothelial cells via a cAMP/PKA-dependent pathway. Br J Pharmacol 154:1247–1253. https://doi.org/10.1038/bjp.2008.194
Zhu R, Huang X, Hu X-Q, Xiao D, Zhang L (2014) Gestational hypoxia increases reactive oxygen species and inhibits steroid hormone-mediated upregulation of Ca2+−activated K+ channel function in uterine arteries. Hypertension 64:415–422. https://doi.org/10.1161/HYPERTENSIONAHA.114.03555
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Neira, F., Neira, N., Torres, J., González-Ortiz, M. (2023). Physiological and Pathophysiological Role of Large-Conductance Calcium-Activated Potassium Channels (BKCa) in HUVECs and Placenta. In: Gonzalez-Ortiz, M. (eds) Advances in Maternal-Fetal Biomedicine. Advances in Experimental Medicine and Biology, vol 1428. Springer, Cham. https://doi.org/10.1007/978-3-031-32554-0_3
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