Preeclampsia (PE) adversely affects as many as 20% of pregnancies in the USA. One of the earliest events is the failure of maternal vascular endothelium vasodilatory function to adapt, with the normal pregnancy-associated increase in NO being blunted or lost. In our previous funding period we used dual imaging of [Ca2+]i and NO in freshly isolated uterine artery endothelium to show that in normal pregnancy, enhancement of Ca2+ signaling is the primary cause of enhanced NO production, and such enhancement depends on specific changes in function of Ca2+ signaling mediators. Sustained Ca2+ entry into UA endothelium occurs through TRPC channels but our preliminary data also suggests the pregnancy enhanced opening of TRPC channels in turn depends on CX43 Gap junction communication, and that such coupling of cells may occur at an electrical level. Our data further suggests membrane hyperpolarization by KCa type channels connects increased Gap junction function to enhance TRPC function in pregnancy. Consistent with this, UAEC show sensitivity to antagonists of KCa function (Apamin and Tram34) with a resulting reduction in Ca2+ signaling. If this model is correct then future therapy for failed adaptation of Ca2+ signaling in PE pregnancy could be achieved by the use of SK or IK type KCa channel agonists. In this renewal we propose to test this model, moving from isolated cells in culture to whole vessels ex vivo to whole animal studies. We will examine 1) Changes in membrane potential and KCa current activity in response to ATP in NP- and P-UAEC in cells at low vs high density, dependence of these changes on gap junction function, and determine the effect of antagonists Apamin and Tram-34 or the selective agonist NS309 on Ca2+ burst activity to implicate KCa channels in this response;2) Examine the effects of these same antagonists and agonists on changes in Ca2+, membrane potential and NO production in intact UA vessels ex vivo;3) determine if the KCa agonist NS309 is comparable to the effects of ATP/UTP in mediating NO dependent increases in blood flow in uterine artery in vivo during pregnancy, and also the extent to which SK and/or IK types of KCa channel mediate this effect. In this way we take our recent advances in mechanistic knowledge of pregnancy adaptation of blood flow to now establish the validity of using KCa channel agonists to maximize this response in vivo in pregnancy and particularly those complicated by PE. Success could have major impact on strategies to improve treatment of human PE pregnancy where this otherwise normal adaptive response has failed and is resistant to current therapies.
Preeclampsia (PE) is a potentially devastating disease of pregnancy that can threaten the life of both mother and the unborn child. It affects as many as 20% of the population. Even mild PE is dangerous and can cause preterm (early) birth and this then gives the baby an increased risk to develop several diseases such as blood pressure, diabetes and obesity as an adult. It is believed that in PE the cells lining the uterine artery blood vessels fail to increase their function as would otherwise happen in normal pregnancy. We have evidence to suggest normal adaptation is due to electrical changes and their failure may be 'fixed'with a specific drug NS309.
The aim of this project is to find out if our suspicions are correct by testing in an animal model. If we are right we may be able to come up with a treatment plan fro PE pregnancy. Having more complete knowledge of how cell function is regulated in pregnancy will certainly take us one step closer to overcoming this potentially devastating disease that effects so many in this country and beyond.
|Sun, Mary Y; Woolley, Joseph C; Blohowiak, Sharon E et al. (2016) Dietary-induced gestational iron deficiency inhibits postnatal tissue iron delivery and postpones the cessation of active nephrogenesis in rats. Reprod Fertil Dev :|
|Boeldt, Derek S; Grummer, Mary A; Yi, FuXian et al. (2015) Phosphorylation of Ser-279/282 and Tyr-265 positions on Cx43 as possible mediators of VEGF-165 inhibition of pregnancy-adapted Ca2+ burst function in ovine uterine artery endothelial cells. Mol Cell Endocrinol 412:73-84|
|Morschauser, Timothy J; Ramadoss, Jayanth; Koch, Jill M et al. (2014) Local effects of pregnancy on connexin proteins that mediate Ca2+-associated uterine endothelial NO synthesis. Hypertension 63:589-94|
|Boeldt, Derek S; Hankes, Amanda C; Alvarez, Roxanne E et al. (2014) Pregnancy programming and preeclampsia: identifying a human endothelial model to study pregnancy-adapted endothelial function and endothelial adaptive failure in preeclamptic subjects. Adv Exp Med Biol 814:27-47|
|Boeldt, Derek S; Grummer, Mary A; Magness, Ronald R et al. (2014) Altered VEGF-stimulated Ca2+ signaling in part underlies pregnancy-adapted eNOS activity in UAEC. J Endocrinol 223:1-11|
|Bird, I M; Boeldt, D S; Krupp, J et al. (2013) Pregnancy, programming and preeclampsia: gap junctions at the nexus of pregnancy-induced adaptation of endothelial function and endothelial adaptive failure in PE. Curr Vasc Pharmacol 11:712-29|
|Yi, Fu-Xian; Boeldt, Derek S; Magness, Ronald R et al. (2011) [Ca2+]i signaling vs. eNOS expression as determinants of NO output in uterine artery endothelium: relative roles in pregnancy adaptation and reversal by VEGF165. Am J Physiol Heart Circ Physiol 300:H1182-93|
|Boeldt, D S; Yi, F X; Bird, I M (2011) eNOS activation and NO function: pregnancy adaptive programming of capacitative entry responses alters nitric oxide (NO) output in vascular endothelium--new insights into eNOS regulation through adaptive cell signaling. J Endocrinol 210:243-58|
|Bird, Ian M (2011) Endothelial nitric oxide synthase activation and nitric oxide function: new light through old windows. J Endocrinol 210:239-41|
|Yi, Fu-Xian; Boeldt, Derek S; Gifford, Shannon M et al. (2010) Pregnancy enhances sustained Ca2+ bursts and endothelial nitric oxide synthase activation in ovine uterine artery endothelial cells through increased connexin 43 function. Biol Reprod 82:66-75|
Showing the most recent 10 out of 11 publications