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22 July 2015 Changes in Ca2 Signaling and Nitric Oxide Output by Human Umbilical Vein Endothelium in Diabetic and Gestational Diabetic Pregnancies
Heather A. Anaya, Fu-Xian Yi, Derek S. Boeldt, Jennifer Krupp, Mary A. Grummer, Dinesh M. Shah, Ian M. Bird
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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 Ca2 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 Ca2 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 Ca2 bursts remains similar, but there is a reduction in overall sustained phase Ca2 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 Ca2 after they were isolated from DM and GDM subjects and maintained in culture for several days. These HUVEC showed differences in the rate of Ca2 bursting, with DM > GDM = control HUVEC. Both GDM- and DM-derived HUVEC showed smaller Ca2 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 Ca2 bursting peak shape and duration are permanently impaired. This may explain why ROS therapy alone is not effective in DM and GDM subjects.

Heather A. Anaya, Fu-Xian Yi, Derek S. Boeldt, Jennifer Krupp, Mary A. Grummer, Dinesh M. Shah, and Ian M. Bird "Changes in Ca2 Signaling and Nitric Oxide Output by Human Umbilical Vein Endothelium in Diabetic and Gestational Diabetic Pregnancies," Biology of Reproduction 93(3), (22 July 2015). https://doi.org/10.1095/biolreprod.115.128645
Received: 27 January 2015; Accepted: 1 July 2015; Published: 22 July 2015
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