Changes in Ca2+ Signaling and Nitric Oxide Output by Human Umbilical Vein Endothelium in Diabetic and Gestational Diabetic Pregnancies.
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.
['Anaya|Heather A|HA|', 'Yi|Fu-Xian|FX|', 'Boeldt|Derek S|DS|', 'Krupp|Jennifer|J|', 'Grummer|Mary A|MA|', 'Shah|Dinesh M|DM|', 'Bird|Ian M|IM|']
D000255:Adenosine Triphosphate D000328:Adult D020013:Calcium Signaling D015331:Cohort Studies D016640:Diabetes, Gestational D004730:Endothelium, Vascular D005260:Female D061307:Human Umbilical Vein Endothelial Cells D006801:Humans D007231:Infant, Newborn D015759:Ionomycin D007476:Ionophores D009569:Nitric Oxide D052250:Nitric Oxide Synthase Type III D011247:Pregnancy D011254:Pregnancy in Diabetics D061251:Primary Cell Culture D011446:Prospective Studies D015398:Signal Transduction D055815:Young Adult
nitric oxide endothelium diabetes pregnancy calcium