Our laboratories focus is to understand more fully the programming events through which normal pregnancy can enhance UA endothelial function in distributing vessels and if vessels can propagate such signals downstream to resistance vessels. In achieving a greater understanding of normal UA endothelial function in pregnancy we can begin to understand the molecular origins of vascular dysfunction associated with failed adaptation in abnormal/diseased pregnancies. This in turn will allow the design of therapeutic strategies to target such errors or minimize their impact through compensatory intervention. Pregnancy is associated with enhanced NO production by UA endothelium, largely due to a remapping of both protein kinase and Ca2+ signaling pathways within the cell. Ca2+ signaling in response to agonists such as ATP is most notably altered in bringing about a sustained and repeated number of Ca2+ bursts and this in turn is paralleled by the longer duration of sustained NO output by the cells. We present preliminary data that these pregnancy specific bursts are due to greater continued interaction of TRPC with IP3-R within the cells and further that such sustained interaction requires functional cell-cell coupling by way of Gap junctions (CX43). Of particular note this is seen more in P-UAEC than in NP-UAEC, and appears to be controlled by phsophorylation of CX43 itself. Our goal in this proposal is to test the hypothesis that Specific Aims A: TRPC. IP3-R and CX43 work together to mediate ATP-stimulated bursts in fCa2+1i in UAEC, in a manner further enhanced by pregnancy. Specifically we will investigate the proposal that:
Specific Aims B: Pregnancy enhanced interactions of TRPC, IP3-R and CX43 to control [Ca2+]i in turn mediate, in part, pregnancy specific increases in eNOS activation by ATP .
Specific Aims C: Translation to Intact Vessels: Pregnancy specific enhancement of interactions of TRPC with IP3-R due to increased CX43 GAP junctions mediates the pregnancy specific enhanced elevation of TCa2+1i bursts and eNOS activity in response to ATP in UA Endo ex vivo.
Aim C in particular is included since our true goal is to establish the basis for the physiologic adaptation occurring in pregnancy. These parallel translational studies will be run on intact Uterine Artery ex vivo throughout the study, in order to establish the mechanisms operating in vivo. Real time imaging of NO and [Ca2+]i will be run to establish in particular if sustained Ca2+ bursts seen in pregnancy are also associated with NO bursts. The possibility that cell-cell communication events initiated in the primary branches (from which UAEC are derived) not only recruit more local cells to the response but allow communicate/signal downstream via CX43 will be considered by analysis of secondary, tertiary and quaternary generations of vessels.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-EMNR-G (05))
Program Officer
Mitchell, Megan S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Wisconsin Madison
Obstetrics & Gynecology
Schools of Medicine
United States
Zip Code
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