Regulation of uterine blood flow during pregnancy is important not only for the growth and survival of the fetus but also for cardiovascular well-being of the mother. Pregnancy is associated with a significant decrease in uterine artery vascular tone and a dramatic increase in uterine blood flow. Previous studies have been focused on adaptation of the endothelium to pregnancy and indicated that increased NO sythesis/release plays an important role in vasodilation of the uterine artery in pregnancy. However, little is known about the adaptation of contractile mechanisms of the uterine artery to pregnancy. The central hypothesis of the proposed studies is that extracellular signal-regulated kinase (ERK) and protein kinase C (PKC) pathways interact in the regulation of uterine artery contractility and play an important role in the adaptation of uterine artery contractile mechanisms to pregnancy. To test this hypothesis, we propose a series of experiments in the uterine arteries obtained from nonpregnant and near-term (~140 Days) pregnant sheep. We found that ERK plays an important role in the regulation of uterine artery contractility, and its effect is agonist-dependent. More importantly, pregnancy selectively enhances the role of ERK in α1-adrenoceptor-mediated contractions and its effect in suppressing protein kinase C-mediated contraction in the uterine artery. Our data indicate that ERK potentiates the thick filament regulatory pathway by enhancing LC20 phosphorylation via increases in [Ca2+] and Ca2+ sensitivity of LC20 phosphorylation. In contrast, ERK attenuates the thin filament regulatory pathway, and suppresses contractions independent of changes in LC20 phosphorylation in the uterine artery. We also found that pregnancy upregulates α1-adrenoceptor-mediated Ca2+ mobilization and LC20 phosphorylation. In contrast, pregnancy downregulates the Ca2+ sensitivity of myofilaments, which is medicated by both thick and then filament pathways. ERK inhibitor, PD098059 significantly inhibited ERK44/42, MYPT1/Thr850 phosphorylation but not MYPT1/Thr696 and CPI-17/Thr38. It suggests that ERK mediated Ca2+ sensitivity is due to, at least, partly though inhibition of MLCP activity. On the other hand, activation of PKC by PDBu results increase in CPI-17/Thr38 phosphorylation and contraction without changes in LC20 phosphorylation. These results imply that PKC-CPI-17-mediated Ca2+ sensitivity of contraction might be through thin filament pathway in the uterine artery.
Ian M. Bird
Charles A. Ducsay
Raymond D. Gilbert
William J. Pearce
Doctor of Philosophy (PhD)
Year Degree Awarded
Date (Title Page)
Library of Congress/MESH Subject Headings
Pregnancy -- blood supply; Uterus -- blood supply; Uterus -- pharmacology; Vasodilation; Protein Kinase C -- pharmacology; Extracellular Signal-Regulated MAP Kinases
Loma Linda University Libraries
This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.
Xiao, DaLiao, "Regulatory Mechanisms of Uterine Artery Contractility : Effect of Pregnancy" (2004). Loma Linda University Electronic Theses, Dissertations & Projects. 1689.
Loma Linda University Electronic Theses and Dissertations
Loma Linda University. Del E. Webb Memorial Library. University Archives