title: The SK3 channel promotes placental vascularization by enhancing secretion of angiogenic factors.
abstract: Proper placental perfusion is essential for fetal exchange of oxygen, nutrients, and waste with the maternal circulation. Impairment of uteroplacental vascular function can lead to pregnancy complications, including preeclampsia and intrauterine growth restriction (IUGR). Potassium channels have been recognized as regulators of vascular proliferation, angiogenesis, and secretion of vasoactive factors, and their dysfunction may underlie pregnancy-related vascular diseases. Overexpression of one channel in particular, the small-conductance calcium-activated potassium channel 3 (SK3), is known to increase vascularization in mice, and mice overexpressing the SK3 channel (SK3(T/T) mice) have a high rate of fetal demise and IUGR. Here, we show that overexpression of SK3 causes fetal loss through abnormal placental vascularization. We previously reported that, at pregnancy day 14, placentas isolated from SK3(T/T) mice are smaller than those obtained from wild-type mice. In this study, histological analysis reveals that SK3(T/-) placentas at this stage have abnormal placental morphology, and microcomputed tomography shows that these placentas have significantly larger and more blood vessels than those from wild-type mice. To identify the mechanism by which these vascularization defects occur, we measured levels of vascular endothelial growth factor (VEGF), placental growth factor, and the soluble form of VEGF receptor 1 (sFlt-1), which must be tightly regulated to ensure proper placental development. Our data reveal that overexpression of SK3 alters systemic and placental ratios of the angiogenic factor VEGF to antiangiogenic factor sFlt-1 throughout pregnancy. Additionally, we observe increased expression of hypoxia-inducing factor 2α in SK3(T/-) placentas. We conclude that the SK3 channel modulates placental vascular development and fetal health by altering VEGF signaling.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Basic Science Research, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Cara C
authors.initials: CC
authors.lastname: Rada
authors.affiliation: Department of Obstetrics and Gynecology, Division of Basic Science Research, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Grace
authors.initials: G
authors.lastname: Murray
authors.affiliation: Department of Obstetrics and Gynecology, Division of Basic Science Research, Washington University School of Medicine, St. Louis, Missouri englands@wustl.edu.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: England
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D005260:Female; D005313:Fetal Death; D005317:Fetal Growth Retardation / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D018919:Neovascularization, Physiologic; D010920:Placenta / Q000098:blood supply / Q000000981:diagnostic imaging / Q000378:metabolism*; D000072483:Placenta Growth Factor; D011225:Pre-Eclampsia / Q000378:metabolism; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D055114:X-Ray Microtomography; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D008565:Membrane Proteins; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins; D011506:Proteins; D051640:Small-Conductance Calcium-Activated Potassium Channels; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D000099162:Endothelial PAS Domain-Containing Protein 1; C496900:Kcnn3 protein, mouse; C000608037:Pgf protein, mouse; C490827:Pigf protein, mouse; C467480:vascular endothelial growth factor A, mouse; C501163:Flt1 protein, mouse
keywords: SK3 channels; angiogenesis; endothelium; placenta; pregnancy