title: Changes in Ca2+ Signaling and Nitric Oxide Output by Human Umbilical Vein Endothelium in Diabetic and Gestational Diabetic Pregnancies.
abstract: Diabetes (DM) complicates 3%-10% of pregnancies, resulting in significant maternal and neonatal morbidity and mortality. DM pregnancies are also associated with vascular dysfunction, including blunted nitric oxide (NO) output, but it remains unclear why. Herein we examine changes in endothelial NO production and its relationship to Ca(2+) signaling in endothelial cells of intact umbilical veins from control versus gestational diabetic (GDM) or preexisting diabetic subjects. We have previously reported that endothelial cells of intact vessels show sustained Ca(2+) bursting in response to ATP, and these bursts drive prolonged NO production. Herein we show that in both GDM and DM pregnancies, the incidence of Ca(2+) bursts remains similar, but there is a reduction in overall sustained phase Ca(2+) mobilization and a reduction in NO output. Further studies show damage has occurred at the level of NOS3 protein itself. Since exposure to DM serum is known to impair normal human umbilical vein endothelial cell (HUVEC) function, we further studied the ability of HUVEC to signal through Ca(2+) after they were isolated from DM and GDM subjects and maintained in culture for several days. These HUVEC showed differences in the rate of Ca(2+) bursting, with DM > GDM = control HUVEC. Both GDM- and DM-derived HUVEC showed smaller Ca(2+) bursts that were less capable of NOS3 activation compared to control HUVEC. We conclude that HUVEC from DM and GDM subjects are reprogrammed such that the Ca(2+) bursting peak shape and duration are permanently impaired. This may explain why ROS therapy alone is not effective in DM and GDM subjects.
authors.affiliation: Perinatal Research Laboratories and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin, Madison, Wisconsin Rush University Medical Center, Section of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Chicago, Illinois.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Anaya
authors.affiliation: Perinatal Research Laboratories and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
authors.forename: Fu-Xian
authors.initials: FX
authors.lastname: Yi
authors.affiliation: Perinatal Research Laboratories and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
authors.forename: Derek S
authors.initials: DS
authors.lastname: Boeldt
authors.affiliation: Perinatal Research Laboratories and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin, Madison, Wisconsin Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Iowa Hospital and Clinics, Iowa City, Iowa.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Krupp
authors.affiliation: Perinatal Research Laboratories and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Grummer
authors.affiliation: Perinatal Research Laboratories and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
authors.forename: Dinesh M
authors.initials: DM
authors.lastname: Shah
authors.affiliation: Perinatal Research Laboratories and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin, Madison, Wisconsin imbird@wisc.edu.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Bird
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D020013:Calcium Signaling; D015331:Cohort Studies; D016640:Diabetes, Gestational / Q000378:metabolism* / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000235:genetics; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000378:metabolism* / Q000503:physiopathology*; D061251:Primary Cell Culture; D011446:Prospective Studies; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D007476:Ionophores; D009569:Nitric Oxide; D015759:Ionomycin; D000255:Adenosine Triphosphate; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III
keywords: calcium; diabetes; endothelium; nitric oxide; pregnancy